La adicción es un trastorno cerebral que se caracteriza por la participación compulsiva en estímulos gratificantes a pesar de las consecuencias adversas. [3] [5] [2] [6] [7] [8] A pesar de la participación de una serie de factores psicosociales, un proceso biológico, uno que es inducido por la exposición repetida a un estímulo adictivo, es la patología central que impulsa el desarrollo y mantenimiento de una adicción, de acuerdo con el "modelo de enfermedad cerebral" de la adicción. [3] Sin embargo, algunos académicos que estudian la adicción argumentan que el modelo de enfermedad cerebral es incompleto y engañoso. [9] [10] [11] [12] [13] [14]
Adiccion | |
---|---|
Otros nombres | Trastorno por consumo de sustancias severo [1] [2] |
Imágenes de tomografía por emisión de positrones del cerebro que comparan el metabolismo cerebral en un individuo sano y en un individuo con adicción a la cocaína | |
Especialidad | Psiquiatría |
Glosario de adicciones y dependencia [3] [4] [5] [2] | |
---|---|
| |
El modelo de enfermedad cerebral postula que la adicción es un trastorno del sistema de recompensa del cerebro que surge a través de mecanismos transcripcionales y epigenéticos y se desarrolla con el tiempo a partir de niveles crónicamente altos de exposición a un estímulo adictivo (p. Ej., Ingerir alimentos, consumir cocaína, participar en actividades sexuales). actividad, participación en actividades culturales de gran emoción como juegos de azar, etc.). [3] [15] [16] DeltaFosB (ΔFosB), un factor de transcripción de genes , es un componente crítico y un factor común en el desarrollo de prácticamente todas las formas de adicción a las drogas y el comportamiento. [15] [16] [17] [18] Dos décadas de investigación sobre el papel de ΔFosB en la adicción han demostrado que surge la adicción y que el comportamiento compulsivo asociado se intensifica o atenúa, junto con la sobreexpresión de ΔFosB en las neuronas espinosas medianas de tipo D1 del núcleo accumbens . [3] [15] [16] [17] Debido a la relación causal entre la expresión de ΔFosB y las adicciones, se usa preclínicamente como un biomarcador de adicción . [3] [15] [17] La expresión de ΔFosB en estas neuronas regula directa y positivamente la autoadministración de fármacos y recompensa la sensibilización a través del refuerzo positivo , al tiempo que disminuye la sensibilidad a la aversión . [nota 1] [3] [15]
La adicción cobra un "costo financiero y humano asombrosamente alto" sobre las personas y la sociedad en su conjunto. [19] [20] [21] En los Estados Unidos, el costo económico total para la sociedad es mayor que el de todos los tipos de diabetes y todos los cánceres combinados. [21] Estos costos surgen de los efectos adversos directos de los medicamentos y los costos de atención médica asociados (p. Ej., Servicios médicos de emergencia y atención ambulatoria y hospitalaria ), complicaciones a largo plazo (p. Ej., Cáncer de pulmón por fumar productos de tabaco , cirrosis hepática y demencia crónica alcohol consumo, y boca de metanfetamina de metanfetamina uso), la pérdida de productividad y asociados de bienestar costes, fatales y no fatales accidentes (por ejemplo, las colisiones de tráfico ), suicidios, homicidios y encarcelamiento, entre otros. [19] [20] [21] [22] Las características clásicas de la adicción incluyen el control deficiente sobre las sustancias o el comportamiento, la preocupación por la sustancia o el comportamiento y el uso continuo a pesar de las consecuencias. [23] Los hábitos y patrones asociados con la adicción se caracterizan típicamente por una gratificación inmediata (recompensa a corto plazo), junto con efectos deletéreos retardados (costos a largo plazo). [24]
Ejemplos de adicciones conductuales incluyen drogas y el alcoholismo , la adicción a la marihuana , adicción a las anfetaminas , la adicción a la cocaína , adicción a la nicotina , adicción a los opiáceos , adicción a la comida , adicción al chocolate , adicción a los videojuegos , la adicción a los juegos de azar , y la adicción sexual . La única adicción conductual reconocida por el DSM-5 y la ICD-10 es la adicción al juego. Con la introducción de la ICD-11 se agregó la adicción a los juegos. [25] El término adicción se usa indebidamente con frecuencia para referirse a otras conductas o trastornos compulsivos, en particular la dependencia , en los medios de comunicación. [26] Una distinción importante entre la drogadicción y la dependencia es que la drogodependencia es un trastorno en el que el cese del consumo de drogas da como resultado un estado desagradable de abstinencia , que puede conducir a un mayor consumo de drogas. [27] La adicción es el uso compulsivo de una sustancia o la realización de un comportamiento que es independiente de la abstinencia. La adicción puede ocurrir en ausencia de dependencia, y la dependencia puede ocurrir en ausencia de adicción, aunque las dos a menudo ocurren juntas.
Neuropsicologia
El control cognitivo y el control de estímulos , que está asociado con el condicionamiento operante y clásico , representan procesos opuestos (es decir, internos frente a externos o ambientales, respectivamente) que compiten por el control de los comportamientos provocados por un individuo. [28] El control cognitivo, y en particular el control inhibitorio sobre la conducta , se ve afectado tanto en la adicción como en el trastorno por déficit de atención con hiperactividad . [29] [30] Las respuestas conductuales impulsadas por estímulos (es decir, el control de estímulos) que están asociadas con un estímulo gratificante particular tienden a dominar el comportamiento de uno en una adicción. [30]
Control de estímulos del comportamiento
Control cognitivo de la conducta
Adicción conductual
El término adicción al comportamiento se refiere a la compulsión de participar en una recompensa natural , que es un comportamiento que es inherentemente gratificante (es decir, deseable o atractivo), a pesar de las consecuencias adversas. [7] [16] [18] La evidencia preclínica ha demostrado que aumentos marcados en la expresión de ΔFosB a través de la exposición repetitiva y excesiva a una recompensa natural induce los mismos efectos conductuales y neuroplasticidad que ocurre en una adicción a las drogas. [16] [31] [32] [33]
Las revisiones tanto de la investigación clínica en humanos como de los estudios preclínicos que involucran a ΔFosB han identificado la actividad sexual compulsiva, específicamente, cualquier forma de relación sexual , como una adicción (es decir, adicción sexual ). [16] [31] Además, se ha demostrado que la sensibilización cruzada de recompensa entre la anfetamina y la actividad sexual, lo que significa que la exposición a una aumenta el deseo por ambas, se ha demostrado preclínica y clínicamente como un síndrome de desregulación de la dopamina ; [16] [31] [32] [33] La expresión de ΔFosB es necesaria para este efecto de sensibilización cruzada, que se intensifica con el nivel de expresión de ΔFosB. [16] [32] [33]
Las revisiones de los estudios preclínicos indican que el consumo frecuente y excesivo a largo plazo de alimentos ricos en grasas o azúcares puede producir una adicción ( adicción a la comida ). [16] [18] Esto puede incluir chocolate . Se sabe que el sabor dulce y los ingredientes farmacológicos de los chocolates crean un fuerte antojo o se sienten "adictivos" por parte del consumidor. [34] Una persona a la que le gusta mucho el chocolate puede referirse a sí misma como adicta al chocolate . El chocolate aún no está reconocido formalmente por el DSM-5 como una adicción diagnosticable. [35]
El juego proporciona una recompensa natural que está asociada con la conducta compulsiva y para la cual los manuales de diagnóstico clínico, a saber, el DSM-5 , han identificado criterios de diagnóstico para una "adicción". [16] Para que el comportamiento de juego de una persona cumpla con los criterios de una adicción, muestra ciertas características, como modificación del estado de ánimo, compulsividad y abstinencia. Existe evidencia de neuroimagen funcional de que el juego activa el sistema de recompensa y la vía mesolímbica en particular. [16] [36] De manera similar, comprar y jugar videojuegos están asociados con comportamientos compulsivos en humanos y también se ha demostrado que activan la vía mesolímbica y otras partes del sistema de recompensa. [16] Sobre la base de esta evidencia, la adicción al juego , adicción a los videojuegos , y la adicción a las compras se clasifican en consecuencia. [16] [36]
Factores de riesgo
Hay una serie de factores de riesgo genéticos y ambientales para desarrollar una adicción, que varían según la población. [3] [37] Los factores de riesgo genéticos y ambientales representan cada uno aproximadamente la mitad del riesgo de que un individuo desarrolle una adicción; [3] Se desconoce la contribución de los factores de riesgo epigenético al riesgo total. [37] Incluso en personas con un riesgo genético relativamente bajo, la exposición a dosis suficientemente altas de una droga adictiva durante un período prolongado (p. Ej., Semanas-meses) puede resultar en una adicción. [3]
Factores genéticos
Desde hace mucho tiempo se ha establecido que los factores genéticos junto con los factores ambientales (por ejemplo, psicosociales) contribuyen de manera significativa a la vulnerabilidad a la adicción. [3] [37] Los estudios epidemiológicos estiman que los factores genéticos representan entre el 40% y el 60% de los factores de riesgo del alcoholismo . [38] Otros estudios han indicado tasas similares de heredabilidad para otros tipos de adicción a las drogas. [39] Knestler planteó la hipótesis en 1964 de que un gen o grupo de genes podría contribuir a la predisposición a la adicción de varias formas. Por ejemplo, los niveles alterados de una proteína normal debido a factores ambientales podrían cambiar la estructura o el funcionamiento de neuronas cerebrales específicas durante el desarrollo. Estas neuronas cerebrales alteradas podrían cambiar la susceptibilidad de un individuo a una experiencia inicial de consumo de drogas. En apoyo de esta hipótesis, los estudios en animales han demostrado que factores ambientales como el estrés pueden afectar el genotipo de un animal. [39]
En general, los datos que implican a genes específicos en el desarrollo de la adicción a las drogas son mixtos para la mayoría de los genes. Una razón para esto puede ser que el caso se deba a un enfoque de la investigación actual sobre variantes comunes. Muchos estudios sobre adicciones se centran en variantes comunes con una frecuencia de alelos superior al 5% en la población general; sin embargo, cuando se asocian con una enfermedad, solo confieren una pequeña cantidad de riesgo adicional con una razón de probabilidades de 1,1 a 1,3 por ciento. Por otro lado, la hipótesis de la variante rara establece que los genes con bajas frecuencias en la población (<1%) confieren un riesgo adicional mucho mayor en el desarrollo de la enfermedad. [40]
Los estudios de asociación de todo el genoma (GWAS) se utilizan para examinar las asociaciones genéticas con la dependencia, la adicción y el consumo de drogas. Estos estudios emplean un enfoque imparcial para encontrar asociaciones genéticas con fenotipos específicos y dan el mismo peso a todas las regiones del ADN, incluidas aquellas que no tienen una relación ostensible con el metabolismo o la respuesta del fármaco. Estos estudios rara vez identifican genes de proteínas previamente descritas a través de modelos animales knockout y análisis de genes candidatos. En cambio, comúnmente se identifican grandes porcentajes de genes involucrados en procesos como la adhesión celular. Esto no quiere decir que los hallazgos anteriores, o los hallazgos de GWAS, sean erróneos. Los efectos importantes de los endofenotipos típicamente no pueden ser capturados por estos métodos. Además, los genes identificados en GWAS para la adicción a las drogas pueden estar involucrados en el ajuste del comportamiento cerebral antes de las experiencias con las drogas, posteriores a ellas o en ambos. [41]
Un estudio que destaca el papel importante que juega la genética en la adicción son los estudios de gemelos. Los gemelos tienen una genética similar y, a veces, idéntica. El análisis de estos genes en relación con la genética ha ayudado a los genetistas a comprender el papel que desempeñan los genes en la adicción. Los estudios realizados en gemelos encontraron que rara vez solo un gemelo tenía una adicción. En la mayoría de los casos en los que al menos uno de los gemelos sufría de una adicción, ambos lo sufrían, y a menudo a la misma sustancia. [42] La adicción cruzada es cuando ya tiene una adicción predispuesta y luego comienza a volverse adicto a algo diferente. Si un miembro de la familia tiene antecedentes de adicción, las posibilidades de que un pariente o una familia cercana desarrolle esos mismos hábitos son mucho mayores que las de uno que no se ha familiarizado con la adicción a una edad temprana. [43] En un estudio reciente realizado por el Instituto Nacional sobre el Abuso de Drogas, de 2002 a 2017, las muertes por sobredosis casi se han triplicado entre hombres y mujeres. En 2017, se informaron 72,306 muertes por sobredosis en los EE. UU. [44] En 2020, las muertes por sobredosis más altas se registraron durante un período de 12 meses. Hubo 81.000 muertes por sobredosis, superando exponencialmente los registros de 2017. [45]
Factores ambientales
Los factores ambientales de riesgo de adicción son las experiencias de un individuo durante su vida que interactúan con la composición genética del individuo para aumentar o disminuir su vulnerabilidad a la adicción. [3] Por ejemplo, después del brote nacional de COVID-19, más personas dejaron de fumar (en lugar de empezar) a fumar; y los fumadores, en promedio, redujeron la cantidad de cigarrillos que consumían. [46] De manera más general, varios factores ambientales diferentes han sido implicados como factores de riesgo de adicción, incluidos varios factores estresantes psicosociales. El Instituto Nacional sobre el Abuso de Drogas (NIDA) cita la falta de supervisión de los padres, la prevalencia del uso de sustancias entre pares, la disponibilidad de drogas y la pobreza como factores de riesgo para el uso de sustancias entre niños y adolescentes. [47] El modelo de adicción a las enfermedades cerebrales postula que la exposición de un individuo a una droga adictiva es el factor de riesgo ambiental más importante para la adicción. [48] Sin embargo, muchos investigadores, incluidos los neurocientíficos, indican que el modelo de enfermedad cerebral presenta una explicación engañosa, incompleta y potencialmente perjudicial de la adicción. [49]
Las experiencias adversas de la niñez (ACE) son varias formas de maltrato y disfunción doméstica que se experimentan en la niñez. El Estudio de Experiencias Adversas en la Infancia realizado por los Centros para el Control y la Prevención de Enfermedades ha demostrado una fuerte relación dosis-respuesta entre las ACE y numerosos problemas de salud, sociales y de comportamiento durante la vida de una persona, incluido el abuso de sustancias . [50] El desarrollo neurológico de los niños puede verse interrumpido permanentemente cuando están expuestos crónicamente a eventos estresantes como abuso físico, emocional o sexual, negligencia física o emocional, presencia de violencia en el hogar o un padre encarcelado o que padece una enfermedad mental. . Como resultado, el funcionamiento cognitivo o la capacidad del niño para hacer frente a las emociones negativas o perturbadoras pueden verse afectadas. Con el tiempo, el niño puede adoptar el uso de sustancias como mecanismo de afrontamiento, especialmente durante la adolescencia . [50] Un estudio de 900 casos judiciales que involucran a niños que experimentaron abuso encontró que una gran cantidad de ellos sufrieron alguna forma de adicción en su adolescencia o vida adulta. [51] Este camino hacia la adicción que se abre a través de experiencias estresantes durante la infancia puede evitarse mediante un cambio en los factores ambientales a lo largo de la vida de un individuo y las oportunidades de ayuda profesional. [51] Si uno tiene amigos o compañeros que se involucran favorablemente en el consumo de drogas, aumentan las posibilidades de que desarrollen una adicción. Los conflictos familiares y el manejo del hogar también son una causa para que uno se involucre en el consumo de alcohol u otras drogas. [52]
Edad
La adolescencia representa un período de vulnerabilidad única para desarrollar una adicción. [53] En la adolescencia, los sistemas de incentivos y recompensas del cerebro maduran mucho antes que el centro de control cognitivo. En consecuencia, esto otorga a los sistemas de incentivos y recompensas una cantidad desproporcionada de poder en el proceso de toma de decisiones conductuales. Por lo tanto, es cada vez más probable que los adolescentes actúen según sus impulsos y se involucren en comportamientos riesgosos y potencialmente adictivos antes de considerar las consecuencias. [54] No solo es más probable que los adolescentes inicien y mantengan el consumo de drogas, sino que una vez adictos son más resistentes al tratamiento y más propensos a recaer. [55] [56]
Las estadísticas han demostrado que quienes comienzan a beber alcohol a una edad más temprana tienen más probabilidades de volverse dependientes más adelante. Aproximadamente el 33% de la población [ ¿dónde? ] probó su primer alcohol entre los 15 y los 17 años, mientras que el 18% lo experimentó antes. En cuanto al abuso o dependencia del alcohol, los números comienzan altos con aquellos que bebieron antes de los 12 años y luego disminuyen después de eso. Por ejemplo, el 16% de los alcohólicos comenzaron a beber antes de cumplir los 12 años, mientras que solo el 9% tocó alcohol por primera vez entre los 15 y los 17 años. Este porcentaje es aún más bajo, del 2.6%, para aquellos que comenzaron el hábito por primera vez después de los 21. [57]
La mayoría de las personas están expuestas y consumen drogas adictivas por primera vez durante la adolescencia. [58] En los Estados Unidos, hubo poco más de 2,8 millones de nuevos usuarios de drogas ilícitas en 2013 (~ 7.800 nuevos usuarios por día); [58] entre ellos, el 54,1% eran menores de 18 años. [58] En 2011, había aproximadamente 20,6 millones de personas en los Estados Unidos mayores de 12 años con una adicción. [59] Más del 90% de las personas con adicción comenzaron a beber, fumar o consumir drogas ilícitas antes de los 18 años. [59]
Trastornos comórbidos
Las personas con trastornos de salud mental comórbidos (es decir, concurrentes) como depresión, ansiedad, trastorno por déficit de atención / hiperactividad (TDAH) o trastorno de estrés postraumático tienen más probabilidades de desarrollar trastornos por uso de sustancias. [60] [61] [62] El NIDA cita el comportamiento agresivo temprano como un factor de riesgo para el uso de sustancias. [47] Un estudio de la Oficina Nacional de Investigación Económica encontró que existe una "conexión definida entre la enfermedad mental y el uso de sustancias adictivas" y la mayoría de los pacientes de salud mental participan en el uso de estas sustancias: 38% de alcohol, 44 % cocaína y 40% cigarrillos. [63]
Factores epigenéticos
Herencia epigenética transgeneracional
Los genes epigenéticos y sus productos (por ejemplo, proteínas) son los componentes clave a través de los cuales las influencias ambientales pueden afectar los genes de un individuo; [37] también sirven como el mecanismo responsable de la herencia epigenética transgeneracional , un fenómeno en el que las influencias ambientales en los genes de un padre pueden afectar los rasgos asociados y los fenotipos conductuales de su descendencia (por ejemplo, respuestas conductuales a los estímulos ambientales). [37] En adicción, los mecanismos epigenéticos juegan un papel central en la fisiopatología de la enfermedad; [3] Se ha observado que algunas de las alteraciones del epigenoma que surgen a través de la exposición crónica a estímulos adictivos durante una adicción pueden transmitirse de generación en generación, afectando a su vez el comportamiento de los hijos (p. Ej., Las respuestas conductuales del niño a las drogas adictivas y recompensas naturales ). [37] [64]
Las clases generales de alteraciones epigenéticas que se han implicado en la herencia epigenética transgeneracional incluyen la metilación del ADN , las modificaciones de histonas y la regulación a la baja o al alza de los microARN . [37] Con respecto a la adicción, se necesita más investigación para determinar las alteraciones epigenéticas hereditarias específicas que surgen de varias formas de adicción en humanos y los fenotipos de comportamiento correspondientes de estas alteraciones epigenéticas que ocurren en la descendencia humana. [37] [64] Según la evidencia preclínica de la investigación con animales , ciertas alteraciones epigenéticas inducidas por la adicción en ratas pueden transmitirse de padres a hijos y producir fenotipos de comportamiento que disminuyen el riesgo de la descendencia de desarrollar una adicción. [nota 2] [37] De manera más general, los fenotipos conductuales hereditarios que se derivan de alteraciones epigenéticas inducidas por la adicción y que se transmiten de padres a hijos pueden servir para aumentar o disminuir el riesgo de que los hijos desarrollen una adicción. [37] [64]
Responsabilidad por abuso
La responsabilidad por abuso, que también se conoce como responsabilidad por adicción, es la propensión a consumir drogas en una situación no médica. Esto suele ser por euforia, cambios de humor o sedación. [65] La responsabilidad por abuso se utiliza cuando la persona que consume las drogas quiere algo que de otro modo no podría obtener. La única forma de conseguirlo es mediante el uso de drogas. Al analizar la responsabilidad por abuso, hay una serie de factores determinantes en el abuso de la droga. Estos factores son: la composición química de la droga, los efectos en el cerebro y la edad, vulnerabilidad y salud (mental y física) de la población en estudio. [65] Hay algunas drogas con una composición química específica que conduce a un alto riesgo de abuso. Estos son: cocaína, heroína, inhalantes, LSD, marihuana, MDMA (éxtasis), metanfetamina, PCP, cannabinoides sintéticos, catinonas sintéticas (sales de baño), tabaco y alcohol. [66]
Mecanismos
Glosario de factores de transcripción | |
---|---|
| |
Cascada de señalización en el núcleo accumbens que resulta en adicción a psicoestimulantes |
El consumo crónico de drogas adictivas provoca alteraciones en la expresión génica en la proyección mesocorticolímbica . [18] [74] [75] Los factores de transcripción más importantes que producen estas alteraciones son ΔFosB , proteína de unión al elemento de respuesta al cAMP ( CREB ) y factor nuclear kappa B ( NF-κB ). [18] ΔFosB es el mecanismo biomolecular más importante en la adicción porque la sobreexpresión de ΔFosB en las neuronas espinosas medianas de tipo D1 en el núcleo accumbens es necesaria y suficiente para muchas de las adaptaciones neuronales y efectos conductuales (p. Ej., Aumentos dependientes de la expresión en autoadministración de drogas y sensibilización por recompensa ) visto en la adicción a las drogas. [18] La expresión de ΔFosB en neuronas espinosas medianas de tipo D1 del núcleo accumbens regula directa y positivamente la autoadministración de fármacos y recompensa la sensibilización a través del refuerzo positivo al tiempo que disminuye la sensibilidad a la aversión . [nota 1] [3] [15] ΔFosB se ha implicado en la mediación de adicciones a muchas drogas diferentes y clases de drogas, incluyendo alcohol , anfetaminas y otras anfetaminas sustituidas , cannabinoides , cocaína , metilfenidato , nicotina , opiáceos , fenilciclidina y propofol , entre otros. [15] [18] [74] [76] [77] ΔJunD , un factor de transcripción, y G9a , una histona metiltransferasa , se oponen a la función de ΔFosB e inhiben los aumentos en su expresión. [3] [18] [78] Los aumentos en la expresión de ΔJunD del núcleo accumbens (a través de la transferencia de genes mediada por vectores virales ) o la expresión de G9a (a través de medios farmacológicos) reducen, o con un gran aumento, incluso pueden bloquear, muchas de las alteraciones neuronales y del comportamiento que resultan del uso crónico de dosis altas de drogas adictivas (es decir, las alteraciones mediadas por ΔFosB). [17] [18]
ΔFosB también juega un papel importante en la regulación de las respuestas conductuales a las recompensas naturales , como la comida apetecible, el sexo y el ejercicio. [18] [79] Las recompensas naturales, como las drogas de abuso, inducen la expresión genética de ΔFosB en el núcleo accumbens, y la adquisición crónica de estas recompensas puede resultar en un estado adictivo patológico similar a través de la sobreexpresión de ΔFosB. [16] [18] [79] En consecuencia, ΔFosB es el factor de transcripción clave involucrado en las adicciones a las recompensas naturales (es decir, adicciones conductuales) también; [18] [16] [79] en particular, ΔFosB en el núcleo accumbens es fundamental para los efectos de refuerzo de la recompensa sexual. [79] La investigación sobre la interacción entre recompensas naturales y de drogas sugiere que los psicoestimulantes dopaminérgicos (p. Ej., Anfetamina ) y el comportamiento sexual actúan sobre mecanismos biomoleculares similares para inducir ΔFosB en el núcleo accumbens y poseen efectos de sensibilización cruzada bidireccional mediados por ΔFosB. [16] [32] [33] Este fenómeno es notable ya que, en los seres humanos, también se ha observado en los seres humanos un síndrome de desregulación de la dopamina , caracterizado por la participación compulsiva inducida por las drogas en las recompensas naturales (específicamente, la actividad sexual, las compras y el juego) en algunas personas que toman medicamentos dopaminérgicos . [dieciséis]
Los inhibidores de ΔFosB (fármacos o tratamientos que se oponen a su acción) pueden ser un tratamiento eficaz para la adicción y los trastornos adictivos. [80]
La liberación de dopamina en el núcleo accumbens juega un papel en las cualidades de refuerzo de muchas formas de estímulos, incluidos los estímulos que refuerzan naturalmente como la comida y el sexo apetitosos. [81] [82] Con frecuencia se observa una alteración de la neurotransmisión de dopamina después del desarrollo de un estado adictivo. [16] En humanos y animales de laboratorio que han desarrollado una adicción, son evidentes alteraciones en la neurotransmisión de dopamina o opioides en el núcleo accumbens y otras partes del cuerpo estriado . [16] Los estudios han encontrado que el uso de ciertas drogas (p. Ej., Cocaína ) afecta las neuronas colinérgicas que inervan el sistema de recompensa , lo que a su vez afecta la señalización de la dopamina en esta región. [83]
Sistema de recompensas
Vía mesocorticolímbica
Acumulación de ΔFosB por uso excesivo de drogas |
Comprender las vías por las que actúan las drogas y cómo las drogas pueden alterar esas vías es clave al examinar la base biológica de la adicción a las drogas. La vía de recompensa, conocida como vía mesolímbica , o su extensión, la vía mesocorticolímbica , se caracteriza por la interacción de varias áreas del cerebro.
- Las proyecciones del área tegmental ventral (VTA) son una red de neuronas dopaminérgicas con receptores de glutamato postsinápticos co-localizados ( AMPAR y NMDAR ). Estas células responden cuando están presentes estímulos indicativos de una recompensa. El VTA apoya el aprendizaje y el desarrollo de la sensibilización y libera DA en el prosencéfalo . [85] Estas neuronas también proyectan y liberan DA en el núcleo accumbens, [86] a través de la vía mesolímbica . Prácticamente todas las drogas que causan adicción a las drogas aumentan la liberación de dopamina en la vía mesolímbica, [87] además de sus efectos específicos.
- El núcleo accumbens (NAcc) es una salida de las proyecciones VTA. El propio núcleo accumbens está formado principalmente por neuronas espinosas medianas GABAérgicas (MSN). [88] El NAcc está asociado con la adquisición y provocación de conductas condicionadas, y está involucrado en el aumento de la sensibilidad a las drogas a medida que avanza la adicción. [85] La sobreexpresión de ΔFosB en el núcleo accumbens es un factor común necesario en prácticamente todas las formas conocidas de adicción; [3] ΔFosB es un fuerte modulador positivo de comportamientos reforzados positivamente . [3]
- La corteza prefrontal , incluidas las cortezas cingulada anterior y orbitofrontal , [89] es otra salida de VTA en la vía mesocorticolímbica; es importante para la integración de información que ayuda a determinar si se provocará un comportamiento. [90] También es fundamental para formar asociaciones entre la experiencia gratificante del uso de drogas y las señales en el medio ambiente. Es importante destacar que estas señales son fuertes mediadores del comportamiento de búsqueda de drogas y pueden desencadenar una recaída incluso después de meses o años de abstinencia. [91]
Otras estructuras cerebrales que están involucradas en la adicción incluyen:
- La amígdala basolateral se proyecta en el NAcc y se cree que también es importante para la motivación. [90]
- El hipocampo está involucrado en la adicción a las drogas, debido a su papel en el aprendizaje y la memoria. Gran parte de esta evidencia proviene de investigaciones que muestran que la manipulación de células en el hipocampo altera los niveles de dopamina en NAcc y las tasas de activación de las células dopaminérgicas VTA. [86]
Papel de la dopamina y el glutamato
La dopamina es el neurotransmisor principal del sistema de recompensa en el cerebro. Desempeña un papel en la regulación del movimiento, la emoción, la cognición, la motivación y los sentimientos de placer. [92] Las recompensas naturales, como comer, así como el consumo de drogas recreativas, provocan la liberación de dopamina y están asociadas con la naturaleza reforzadora de estos estímulos. [92] [93] Casi todas las drogas adictivas, directa o indirectamente, actúan sobre el sistema de recompensa del cerebro aumentando la actividad dopaminérgica. [94]
La ingesta excesiva de muchos tipos de drogas adictivas da como resultado la liberación repetida de grandes cantidades de dopamina, lo que a su vez afecta la vía de recompensa directamente a través de una mayor activación del receptor de dopamina . Niveles prolongados y anormalmente altos de dopamina en la hendidura sináptica pueden inducir una regulación negativa del receptor en la vía neural. La regulación a la baja de los receptores de dopamina mesolímbicos puede resultar en una disminución de la sensibilidad a los reforzadores naturales. [92]
El comportamiento de búsqueda de fármacos es inducido por proyecciones glutamatérgicas desde la corteza prefrontal hacia el núcleo accumbens. Esta idea está respaldada por datos de experimentos que muestran que el comportamiento de búsqueda de fármacos se puede prevenir tras la inhibición de los receptores de glutamato AMPA y la liberación de glutamato en el núcleo accumbens. [89]
Recompensa la sensibilización
Gen diana | Expresión de destino | Efectos neuronales | Efectos conductuales |
---|---|---|---|
c-Fos | ↓ | Interruptor molecular que permite la inducción crónica de ΔFosB [nota 3] | - |
dinorfina | ↓ [nota 4] | • Regulación a la baja del circuito de retroalimentación de opioides κ | • Mayor recompensa por drogas |
NF-κB | ↑ | • Expansión de los procesos dendríticos de NAcc • Respuesta inflamatoria NF-κB en la NAcc • Respuesta inflamatoria NF-κB en la PC | • Mayor recompensa por fármacos • Mayor recompensa por fármacos • Sensibilización locomotora |
GluR2 | ↑ | • Disminución de la sensibilidad al glutamato. | • Mayor recompensa por drogas |
Cdk5 | ↑ | • Fosforilación de la proteína sináptica GluR1 • Expansión de los procesos dendríticos de NAcc | Recompensa de drogas disminuida (efecto neto) |
La sensibilización a la recompensa es un proceso que provoca un aumento en la cantidad de recompensa (específicamente, prominencia de incentivo [nota 5] ) que el cerebro asigna a un estímulo gratificante (p. Ej., Una droga). En términos simples, cuando ocurre la sensibilización de recompensa a un estímulo específico (por ejemplo, una droga), aumenta el "querer" o el deseo de un individuo por el estímulo en sí y sus señales asociadas . [97] [96] [98] La sensibilización de recompensa ocurre normalmente después de niveles crónicamente altos de exposición al estímulo. Se ha demostrado que la expresión de ΔFosB (DeltaFosB) en neuronas espinosas medianas de tipo D1 en el núcleo accumbens regula directa y positivamente la sensibilización a la recompensa que involucra drogas y recompensas naturales. [3] [15] [17]
El "deseo inducido por señales" o "el deseo provocado por señales", una forma de deseo que ocurre en la adicción, es responsable de la mayor parte del comportamiento compulsivo que exhiben los adictos. [96] [98] Durante el desarrollo de una adicción, la asociación repetida de estímulos por lo demás neutrales e incluso no gratificantes con el consumo de drogas desencadena un proceso de aprendizaje asociativo que hace que estos estímulos previamente neutrales actúen como reforzadores positivos condicionados del uso de drogas adictivas ( es decir, estos estímulos comienzan a funcionar como señales de drogas ). [96] [99] [98] Como reforzadores positivos condicionados del consumo de drogas, a estos estímulos previamente neutrales se les asigna una prominencia de incentivo (que se manifiesta como un deseo), a veces en niveles patológicamente altos debido a la sensibilización a la recompensa, que puede transferirse al reforzador primario (p. ej., el uso de una droga adictiva) con la que se emparejó originalmente. [96] [99] [98]
La investigación sobre la interacción entre recompensas naturales y de drogas sugiere que los psicoestimulantes dopaminérgicos (p. Ej., Anfetamina ) y el comportamiento sexual actúan sobre mecanismos biomoleculares similares para inducir ΔFosB en el núcleo accumbens y poseen un efecto de sensibilización cruzada de recompensa bidireccional [nota 6] que está mediado por ΔFosB. [16] [32] [33] En contraste con el efecto de sensibilización de recompensa de ΔFosB, la actividad transcripcional de CREB disminuye la sensibilidad del usuario a los efectos de recompensa de la sustancia. La transcripción de CREB en el núcleo accumbens está implicada en la dependencia psicológica y los síntomas que implican una falta de placer o motivación durante la abstinencia de la droga . [3] [84] [95]
El conjunto de proteínas conocido como " reguladores de la señalización de la proteína G " (RGS), en particular RGS4 y RGS9-2 , se ha implicado en la modulación de algunas formas de sensibilización a opioides, incluida la sensibilización por recompensa. [100]
Forma de neuroplasticidad o plasticidad conductual. | Tipo de reforzador | Fuentes | |||||
---|---|---|---|---|---|---|---|
Opiáceos | Psicoestimulantes | Alimentos ricos en grasas o azúcares | Relaciones sexuales | Ejercicio físico (aeróbico) | Enriquecimiento ambiental | ||
Expresión de ΔFosB en MSN de tipo D1 del núcleo accumbens | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [dieciséis] |
Plasticidad conductual | |||||||
Escalada de ingesta | sí | sí | sí | [dieciséis] | |||
Sensibilización cruzada con psicoestimulantes | sí | No aplica | sí | sí | Atenuado | Atenuado | [dieciséis] |
Psicoestimulantes autoadministración | ↑ | ↑ | ↓ | ↓ | ↓ | [dieciséis] | |
Preferencia de lugar condicionada por psicoestimulantes | ↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [dieciséis] |
Restablecimiento del comportamiento de búsqueda de drogas | ↑ | ↑ | ↓ | ↓ | [dieciséis] | ||
Plasticidad neuroquímica | |||||||
Fosforilación de CREB en el núcleo accumbens | ↓ | ↓ | ↓ | ↓ | ↓ | [dieciséis] | |
Respuesta de dopamina sensibilizada en el núcleo accumbens | No | sí | No | sí | [dieciséis] | ||
Señalización de dopamina estriatal alterada | ↓ DRD2 , ↑ DRD3 | ↑ DRD1 , ↓ DRD2 , ↑ DRD3 | ↑ DRD1 , ↓ DRD2 , ↑ DRD3 | ↑ DRD2 | ↑ DRD2 | [dieciséis] | |
Señalización de opioides estriatal alterada | Sin cambios o con ↑ μ-receptores opioides | ↑ receptores μ-opioides ↑ receptores κ-opioides | ↑ receptores μ-opioides | ↑ receptores μ-opioides | Ningún cambio | Ningún cambio | [dieciséis] |
Cambios en los péptidos opioides estriatales | ↑ dinorfina Sin cambios: encefalina | ↑ dinorfina | ↓ encefalina | ↑ dinorfina | ↑ dinorfina | [dieciséis] | |
Plasticidad sináptica mesocorticolímbica | |||||||
Número de dendritas en el núcleo accumbens | ↓ | ↑ | ↑ | [dieciséis] | |||
Densidad de la columna dendrítica en el núcleo accumbens | ↓ | ↑ | ↑ | [dieciséis] |
Mecanismos neuroepigenéticos
La regulación epigenética alterada de la expresión génica dentro del sistema de recompensa del cerebro juega un papel importante y complejo en el desarrollo de la adicción a las drogas. [78] [101] Las drogas adictivas se relacionan con tres tipos de modificaciones epigenéticas dentro de las neuronas. [78] Estas son (1) modificaciones de histonas , (2) metilación epigenética de ADN en sitios CpG en (o adyacentes a) genes particulares, y (3) regulación epigenética a la baja o al alza de microARN que tienen genes diana particulares. [78] [18] [101] Como ejemplo, mientras que cientos de genes en las células del núcleo accumbens (NAc) exhiben modificaciones de histonas después de la exposición al fármaco, en particular, estados alterados de acetilación y metilación de residuos de histonas [101] - la mayoría de los demás los genes de las células NAc no muestran tales cambios. [78]
Diagnóstico
La quinta edición del Manual diagnóstico y estadístico de trastornos mentales (DSM-5) utiliza el término " trastorno por uso de sustancias " para referirse a un espectro de trastornos relacionados con el uso de drogas. El DSM-5 elimina los términos " abuso " y "dependencia" de las categorías de diagnóstico, y en su lugar utiliza los especificadores de leve , moderado y severo para indicar la extensión del uso desordenado. Estos especificadores están determinados por el número de criterios de diagnóstico presentes en un caso dado. En el DSM-5, el término adicción a las drogas es sinónimo de trastorno grave por uso de sustancias . [1] [2]
El DSM-5 introdujo una nueva categoría de diagnóstico para las adicciones conductuales; sin embargo, el juego problemático es la única condición incluida en esa categoría en la 5ª edición. [26] El trastorno de los juegos de Internet se enumera como una "condición que requiere más estudio" en el DSM-5. [102]
Las ediciones pasadas han utilizado la dependencia física y el síndrome de abstinencia asociado para identificar un estado adictivo. La dependencia física ocurre cuando el cuerpo se ha adaptado incorporando la sustancia a su funcionamiento "normal", es decir, logra la homeostasis , y por lo tanto, los síntomas de abstinencia física ocurren al dejar de consumirla. [103] La tolerancia es el proceso mediante el cual el cuerpo se adapta continuamente a la sustancia y requiere cantidades cada vez mayores para lograr los efectos originales. La abstinencia se refiere a los síntomas físicos y psicológicos que se experimentan al reducir o suspender una sustancia de la que el cuerpo se ha vuelto dependiente. Los síntomas de abstinencia generalmente incluyen, entre otros, dolores corporales, ansiedad , irritabilidad , antojos intensos por la sustancia, náuseas , alucinaciones , dolores de cabeza , sudores fríos, temblores y convulsiones.
Los investigadores médicos que estudian activamente la adicción han criticado la clasificación de adicción del DSM por ser defectuosa e incluir criterios de diagnóstico arbitrarios. [27] Escribiendo en 2013, el director del Instituto Nacional de Salud Mental de los Estados Unidos discutió la invalidez de la clasificación de trastornos mentales del DSM-5: [104]
Si bien DSM se ha descrito como una "Biblia" para el campo, es, en el mejor de los casos, un diccionario que crea un conjunto de etiquetas y define cada una. La fortaleza de cada una de las ediciones de DSM ha sido la "confiabilidad": cada edición ha asegurado que los médicos usen los mismos términos de la misma manera. La debilidad es su falta de validez. A diferencia de nuestras definiciones de cardiopatía isquémica, linfoma o SIDA, los diagnósticos del DSM se basan en un consenso sobre grupos de síntomas clínicos, no en ninguna medida objetiva de laboratorio. En el resto de la medicina, esto equivaldría a crear sistemas de diagnóstico basados en la naturaleza del dolor torácico o la calidad de la fiebre.
Dado que la adicción se manifiesta en cambios estructurales en el cerebro, es posible que las exploraciones de neuroimagen no invasivas obtenidas mediante resonancia magnética puedan usarse para ayudar a diagnosticar la adicción en el futuro. [105] Como biomarcador de diagnóstico , la expresión de ΔFosB podría usarse para diagnosticar una adicción en humanos, pero esto requeriría una biopsia cerebral y, por lo tanto, no se usa en la práctica clínica.
Tratamiento
Según una revisión, "para que sean efectivos, todos los tratamientos farmacológicos o biológicos para la adicción deben integrarse en otras formas establecidas de rehabilitación de adicciones, como la terapia cognitivo-conductual, la psicoterapia individual y grupal, las estrategias de modificación de la conducta , los doce pasos programas e instalaciones de tratamiento residencial ". [8]
Terapia de comportamiento
Una revisión metaanalítica sobre la eficacia de varias terapias conductuales para el tratamiento de adicciones a las drogas y conductuales encontró que la terapia cognitivo conductual (p. Ej., Prevención de recaídas y manejo de contingencias ), entrevistas motivacionales y un enfoque de refuerzo comunitario fueron intervenciones efectivas con tamaños de efecto moderados. [106]
La evidencia clínica y preclínica indica que el ejercicio aeróbico constante, especialmente el ejercicio de resistencia (p. Ej., Correr un maratón ), en realidad previene el desarrollo de ciertas adicciones a las drogas y es un tratamiento complementario eficaz para la adicción a las drogas y, en particular, para la adicción a los psicoestimulantes. [16] [107] [108] [109] [110] El ejercicio aeróbico constante en función de la magnitud (es decir, por duración e intensidad) reduce el riesgo de adicción a las drogas, que parece ocurrir mediante la reversión de la neuroplasticidad relacionada con la adicción inducida por las drogas. [16] [108] Una revisión señaló que el ejercicio puede prevenir el desarrollo de adicción a las drogas al alterar la inmunorreactividad de ΔFosB o c-Fos en el cuerpo estriado u otras partes del sistema de recompensa . [110] El ejercicio aeróbico disminuye la autoadministración de fármacos, reduce la probabilidad de recaída e induce efectos opuestos en la señalización del receptor de dopamina D 2 (DRD2) estriatal (aumento de la densidad de DRD2) a los inducidos por adicciones a varias clases de fármacos (disminución de la densidad de DRD2) . [16] [108] En consecuencia, el ejercicio aeróbico constante puede conducir a mejores resultados del tratamiento cuando se usa como tratamiento complementario para la adicción a las drogas. [16] [108] [109]
Medicamento
Adicción al alcohol
El alcohol, como los opioides, puede inducir un estado severo de dependencia física y producir síntomas de abstinencia como el delirium tremens . Debido a esto, el tratamiento para la adicción al alcohol generalmente implica un enfoque combinado que trata simultáneamente la dependencia y la adicción. Las benzodiazepinas tienen la mayor y mejor base de evidencia en el tratamiento de la abstinencia de alcohol y se consideran el estándar de oro de la desintoxicación del alcohol . [111]
Los tratamientos farmacológicos para la adicción al alcohol incluyen fármacos como naltrexona (antagonista opioide), disulfiram , acamprosato y topiramato . [112] [113] En lugar de sustituir el alcohol, estas drogas están destinadas a afectar el deseo de beber, ya sea reduciendo directamente los antojos como con acamprosato y topiramato, o produciendo efectos desagradables cuando se consume alcohol, como con disulfiram. Estos medicamentos pueden ser efectivos si se mantiene el tratamiento, pero el cumplimiento puede ser un problema, ya que los pacientes alcohólicos a menudo se olvidan de tomar sus medicamentos o suspenden su uso debido a efectos secundarios excesivos. [114] [115] Según una revisión de la Colaboración Cochrane , se ha demostrado que el antagonista opioide naltrexona es un tratamiento eficaz para el alcoholismo, con efectos que duran de tres a doce meses después del final del tratamiento. [116]
Adicciones conductuales
La adicción al comportamiento es una condición tratable. Las opciones de tratamiento incluyen psicoterapia y psicofarmacoterapia (es decir, medicamentos) o una combinación de ambas. La terapia cognitivo-conductual (TCC) es la forma más común de psicoterapia que se usa para tratar las adicciones conductuales; se enfoca en identificar patrones que desencadenan el comportamiento compulsivo y realizar cambios en el estilo de vida para promover comportamientos más saludables. Debido a que la terapia cognitivo-conductual se considera una terapia a corto plazo, el número de sesiones de tratamiento normalmente varía de cinco a veinte. Durante la sesión, los terapeutas guiarán a los pacientes a través de los temas de identificar el problema, tomar conciencia de los pensamientos que rodean el problema, identificar cualquier pensamiento negativo o falso y remodelar dicho pensamiento negativo y falso. Si bien la TCC no cura la adicción al comportamiento, sí ayuda a sobrellevar la afección de manera saludable. Actualmente, no hay medicamentos aprobados para el tratamiento de las adicciones conductuales en general, pero algunos medicamentos utilizados para el tratamiento de la adicción a las drogas también pueden ser beneficiosos con adicciones conductuales específicas. [36] [117] Cualquier trastorno psiquiátrico no relacionado debe mantenerse bajo control y diferenciarse de los factores contribuyentes que causan la adicción.
Adicción a los cannabinoides
A partir de 2010[actualizar], no existen intervenciones farmacológicas efectivas para la adicción a los cannabinoides. [118] Una revisión de 2013 sobre la adicción a los cannabinoides señaló que el desarrollo de agonistas del receptor CB1 que han reducido la interacción con la señalización de la β-arrestina 2 podría ser terapéuticamente útil. [119]
Adicción a la nicotina
Otra área en la que el tratamiento farmacológico se ha utilizado ampliamente es en el tratamiento de la adicción a la nicotina , que normalmente implica el uso de terapia de reemplazo de nicotina , antagonistas del receptor nicotínico o agonistas parciales del receptor nicotínico . [120] [121] Ejemplos de fármacos que actúan sobre los receptores nicotínicos y que se han utilizado para tratar la adicción a la nicotina incluyen antagonistas como el bupropión y el agonista parcial vareniclina . [120] [121]
Adicción a los opioides
Los opioides causan dependencia física y el tratamiento generalmente aborda tanto la dependencia como la adicción.
La dependencia física se trata con medicamentos de reemplazo como suboxona o subutex (ambos contienen los ingredientes activos buprenorfina ) y metadona . [122] [123] Aunque estos fármacos perpetúan la dependencia física, el objetivo del mantenimiento de los opiáceos es proporcionar una medida de control sobre el dolor y los antojos. El uso de medicamentos de reemplazo aumenta la capacidad del individuo adicto para funcionar normalmente y elimina las consecuencias negativas de obtener sustancias controladas de manera ilícita. Una vez que se estabiliza una dosis prescrita, el tratamiento entra en las fases de mantenimiento o disminución. En los Estados Unidos, la terapia de reemplazo de opiáceos está estrictamente regulada en las clínicas de metadona y bajo la legislación DATA 2000 . En algunos países, otros derivados opioides como la dihidrocodeína , [124] la dihidroetorfina [125] e incluso la heroína [126] [127] se utilizan como drogas sustitutivas de los opiáceos ilegales que se venden en la calle, con diferentes prescripciones según las necesidades de cada paciente. . El baclofeno ha llevado a una reducción exitosa de los antojos de estimulantes, alcohol y opioides, y también alivia el síndrome de abstinencia de alcohol . Muchos pacientes han declarado que "se volvieron indiferentes al alcohol" o "indiferentes a la cocaína" durante la noche después de comenzar la terapia con baclofeno. [128] Algunos estudios muestran la interconexión entre la desintoxicación de drogas opioides y la mortalidad por sobredosis. [129]
Adicción a los psicoestimulantes
En mayo de 2014[actualizar], no existe una farmacoterapia eficaz para ninguna forma de adicción a los psicoestimulantes. [8] [130] [131] [132] Revisiones de 2,015, 2,016, y 2,018 indicado que TAAR1 - agonistas selectivos tienen un potencial terapéutico significativo como tratamiento para adicciones psicoestimulantes; [133] [134] [135] sin embargo, a partir de 2018[actualizar], los únicos compuestos que se sabe que funcionan como agonistas selectivos de TAAR1 son los fármacos experimentales . [133] [134] [135]
Investigar
Las investigaciones indican que las vacunas que utilizan anticuerpos monoclonales antidrogas pueden mitigar el refuerzo positivo inducido por fármacos al evitar que el fármaco se mueva a través de la barrera hematoencefálica ; [136] sin embargo, las terapias actuales basadas en vacunas solo son efectivas en un subconjunto relativamente pequeño de individuos. [136] [137] A noviembre de 2015[actualizar], las terapias basadas en vacunas se están probando en ensayos clínicos en humanos como tratamiento para la adicción y como medida preventiva contra las sobredosis de drogas que involucran nicotina, cocaína y metanfetamina. [136]
El nuevo estudio muestra que la vacuna también puede salvar vidas durante una sobredosis de drogas . En este caso, la idea es que el cuerpo responda a la vacuna produciendo anticuerpos rápidamente para evitar que los opioides accedan al cerebro. [138]
Desde la adicción implica anormalidades en glutamato y GABAérgicas neurotransmisión, [139] [140] receptores asociados con estos neurotransmisores (por ejemplo, los receptores de AMPA , receptores de NMDA y GABA B receptores ) son potenciales dianas terapéuticas para las adicciones. [139] [140] [141] [142] La N-acetilcisteína , que afecta los receptores metabotrópicos de glutamato y los receptores NMDA, ha mostrado algún beneficio en estudios preclínicos y clínicos que involucran adicciones a la cocaína, heroína y cannabinoides. [139] También puede ser útil como terapia complementaria para las adicciones a los estimulantes de tipo anfetamínico , pero se requiere más investigación clínica. [139]
Las revisiones médicas actuales de la investigación con animales de laboratorio han identificado una clase de fármaco - inhibidores de histona desacetilasa clase I [nota 7] - que inhibe indirectamente la función y aumenta aún más la expresión de ΔFosB accumbal al inducir la expresión de G9a en el núcleo accumbens después de un uso prolongado. [17] [78] [143] [101] Estas revisiones y la evidencia preliminar posterior que utilizó la administración oral o la administración intraperitoneal de la sal sódica del ácido butírico u otros inhibidores de HDAC de clase I durante un período prolongado indican que estos fármacos tienen eficacia para reducir comportamiento adictivo en animales de laboratorio [nota 8] que han desarrollado adicciones al etanol, psicoestimulantes (es decir, anfetamina y cocaína), nicotina y opiáceos; [78] [101] [144] [145] sin embargo, se han realizado pocos ensayos clínicos con adictos humanos y cualquier inhibidor de HDAC clase I para probar la eficacia del tratamiento en humanos o identificar un régimen de dosificación óptimo. [nota 9]
La terapia genética para la adicción es un área de investigación activa. Una línea de investigación en terapia génica implica el uso de vectores virales para aumentar la expresión de las proteínas receptoras de dopamina D2 en el cerebro. [147] [148] [149] [150] [151]
Epidemiología
Debido a las variaciones culturales, la proporción de personas que desarrollan una adicción a las drogas o al comportamiento dentro de un período de tiempo específico (es decir, la prevalencia ) varía con el tiempo, según el país y a través de la demografía de la población nacional (p. Ej., Por grupo de edad, nivel socioeconómico, etc. .). [37]
Asia
The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socioeconomic factors but also biological factors influence drinking behavior.[152]
The overall prevalence of smartphone ownership is 62%, ranging from 41% in China to 84% in South Korea. Moreover, participation in online gaming ranges from 11% in China to 39% in Japan. Hong Kong has the highest number of adolescents reporting daily or above Internet use (68%). Internet addiction disorder is highest in the Philippines, according to both the IAT (Internet Addiction Test) – 5% and the CIAS-R (Revised Chen Internet Addiction Scale) – 21%.[153]
Australia
The prevalence of substance abuse disorder among Australians was reported at 5.1% in 2009.[154]
Europe
In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8, 0.77, 0.37 and 0.35% in 2017 cannabis, amphetamine, opioid and cocaine use. The mortality rates for alcohol and illicit drugs were highest in Eastern Europe.[155]
United States
Based upon representative samples of the US youth population in 2011, the lifetime prevalence[note 10] of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively.[20] Based upon representative samples of the US adult population in 2011, the 12 month prevalence of alcohol and illicit drug addictions were estimated at roughly 12% and 2–3% respectively.[20] The lifetime prevalence of prescription drug addictions is currently around 4.7%.[156]
As of 2016,[update] about 22 million people in the United States need treatment for an addiction to alcohol, nicotine, or other drugs.[21][157] Only about 10%, or a little over 2 million, receive any form of treatments, and those that do generally do not receive evidence-based care.[21][157] One-third of inpatient hospital costs and 20% of all deaths in the US every year are the result of untreated addictions and risky substance use.[21][157] In spite of the massive overall economic cost to society, which is greater than the cost of diabetes and all forms of cancer combined, most doctors in the US lack the training to effectively address a drug addiction.[21][157]
Another review listed estimates of lifetime prevalence rates for several behavioral addictions in the United States, including 1–2% for compulsive gambling, 5% for sexual addiction, 2.8% for food addiction, and 5–6% for compulsive shopping.[16] A systematic review indicated that the time-invariant prevalence rate for sexual addiction and related compulsive sexual behavior (e.g., compulsive masturbation with or without pornography, compulsive cybersex, etc.) within the United States ranges from 3–6% of the population.[31]
According to a 2017 poll conducted by the Pew Research Center, almost half of US adults know a family member or close friend who has struggled with a drug addiction at some point in their life.[158]
In 2019, opioid addiction was acknowledged as a national crisis in the United States.[159] An article in The Washington Post stated that "America’s largest drug companies flooded the country with pain pills from 2006 through 2012, even when it became apparent that they were fueling addiction and overdoses."
South America
The realities of opioid use and abuse in Latin America may be deceptive if observations are limited to epidemiological findings. In the United Nations Office on Drugs and Crime report,[160] although South America produced 3% of the world's morphine and heroin and 0.01% of its opium, prevalence of use is uneven. According to the Inter-American Commission on Drug Abuse Control, consumption of heroin is low in most Latin American countries, although Colombia is the area's largest opium producer. Mexico, because of its border with the United States, has the highest incidence of use.[161]
Teorías de la personalidad
Personality theories of addiction are psychological models that associate personality traits or modes of thinking (i.e., affective states) with an individual's proclivity for developing an addiction. Data analysis demonstrates that there is a significant difference in the psychological profiles of drug users and non-users and the psychological predisposition to using different drugs may be different.[162] Models of addiction risk that have been proposed in psychology literature include an affect dysregulation model of positive and negative psychological affects, the reinforcement sensitivity theory model of impulsiveness and behavioral inhibition, and an impulsivity model of reward sensitization and impulsiveness.[163][164][165][166][167]
Los sufijos "-holic" y "-holism"
In contemporary modern English "-holic" is a suffix that can be added to a subject to denote an addiction to it. It was extracted from the word alcoholism (one of the first addictions to be widely identified both medically and socially) (correctly the root "wikt:alcohol" plus the suffix "-ism") by misdividing or rebracketing it into "alco" and "-holism". (Another such misdivision is interpreting "helicopter" as "heli-copter" rather than the etymologically correct "helico-pter", giving rise to such derived words as "heliport" and "jetcopter".[168]) There are correct medico-legal terms for such addictions: dipsomania is the medico-legal term for alcoholism;[169] other examples are in this table:
Colloquial term | Addiction to | Medico-legal term |
---|---|---|
danceaholic | dance | choreomania |
workaholic | work | ergomania |
sexaholic | sex | erotomania, satyromania, nymphomania |
sugarholic | sugar | saccharomania |
chocoholic | chocolate |
The term "-holism" is not an accepted medical term, but is a fairly prominent neologism. As such, despite its widespread usage, it lacks a formal definition. The term can be used in many ways ranging from describing a physical or psychological dependency to something (ex. sexaholism[170][171]), to a tendency to do something obsessively (ex. workaholism,[172] shopaholism[173]). "-Holism" can also be used by someone to express a strong passion for or interest in something. For example, professional wrestler Chris Jericho would refer to his fans as Jerichoholics.[174]
Ver también
- Autonomic nervous system
- Binge drinking
- Binge eating disorder
- Discrimination against drug addicts
- Dopaminergic pathways
- Habit
- Pavlovian-instrumental transfer
- Philosophy of medicine
- Substance abuse
- Substance dependence
Notas
- ^ a b A decrease in aversion sensitivity, in simpler terms, means that an individual's behavior is less likely to be influenced by undesirable outcomes.
- ^ According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of epigenetic marks that occur in addiction, alterations in histone acetylation – specifically, di-acetylation of lysine residues 9 and 14 on histone 3 (i.e., H3K9ac2 and H3K14ac2) in association with BDNF gene promoters – have been shown to occur within the medial prefrontal cortex (mPFC), testes, and sperm of cocaine-addicted male rats.[37] These epigenetic alterations in the rat mPFC result in increased BDNF gene expression within the mPFC, which in turn blunts the rewarding properties of cocaine and reduces cocaine self-administration.[37] The male but not female offspring of these cocaine-exposed rats inherited both epigenetic marks (i.e., di-acetylation of lysine residues 9 and 14 on histone 3) within mPFC neurons, the corresponding increase in BDNF expression within mPFC neurons, and the behavioral phenotype associated with these effects (i.e., a reduction in cocaine reward, resulting in reduced cocaine-seeking by these male offspring).[37] Consequently, the transmission of these two cocaine-induced epigenetic alterations (i.e., H3K9ac2 and H3K14ac2) in rats from male fathers to male offspring served to reduce the offspring's risk of developing an addiction to cocaine.[37] As of 2018,[update] neither the heritability of these epigenetic marks in humans nor the behavioral effects of the marks within human mPFC neurons has been established.[37]
- ^ In other words, c-Fos repression allows ΔFosB to more rapidly accumulate within the D1-type medium spiny neurons of the nucleus accumbens because it is selectively induced in this state.[3] Prior to c-Fos repression, all Fos family proteins (e.g., c-Fos, Fra1, Fra2, FosB, and ΔFosB) are induced together, with ΔFosB expression increasing to a lesser extent.[3]
- ^ According to two medical reviews, ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[15][95] this table entry reflects only a decrease.
- ^ Incentive salience, the "motivational salience" for a reward, is a "desire" or "want" attribute, which includes a motivational component, that the brain assigns to a rewarding stimulus.[96][97] As a consequence, incentive salience acts as a motivational "magnet" for a rewarding stimulus that commands attention, induces approach, and causes the rewarding stimulus to be sought out.[96]
- ^ In simplest terms, this means that when either amphetamine or sex is perceived as more alluring or desirable through reward sensitization, this effect occurs with the other as well.
- ^ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;[143][101] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
- ^ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.[78][101][144]
- ^ Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.[146]
- ^ The lifetime prevalence of an addiction is the percentage of individuals in a population that developed an addiction at some point in their life.
- Image legend
- ^ Ion channelG proteins & linked receptors(Text color) Transcription factors
Referencias
- ^ a b "Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health" (PDF). Office of the Surgeon General. US Department of Health and Human Services. November 2016. pp. 35–37, 45, 63, 155, 317, 338. Retrieved 28 January 2017.
- ^ a b c d Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013.
Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder. - ^ a b c d e f g h i j k l m n o p q r s t u Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410.
Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
- ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
- ^ a b "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
- ^ Angres DH, Bettinardi-Angres K (October 2008). "The disease of addiction: origins, treatment, and recovery". Disease-A-Month. 54 (10): 696–721. doi:10.1016/j.disamonth.2008.07.002. PMID 18790142.
- ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–65, 375. ISBN 978-0-07-148127-4.
The defining feature of addiction is compulsive, out-of-control drug use, despite negative consequences. ...
compulsive eating, shopping, gambling, and sex – so-called "natural addictions" – Indeed, addiction to both drugs and behavioral rewards may arise from similar dysregulation of the mesolimbic dopamine system. - ^ a b c Taylor SB, Lewis CR, Olive MF (February 2013). "The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans". Subst. Abuse Rehabil. 4: 29–43. doi:10.2147/SAR.S39684. PMC 3931688. PMID 24648786.
Initial drug use can be attributed to the ability of the drug to act as a reward (ie, a pleasurable emotional state or positive reinforcer), which can lead to repeated drug use and dependence.8,9 A great deal of research has focused on the molecular and neuroanatomical mechanisms of the initial rewarding or reinforcing effect of drugs of abuse. ... At present, no pharmacological therapy has been approved by the FDA to treat psychostimulant addiction. Many drugs have been tested, but none have shown conclusive efficacy with tolerable side effects in humans.172 ... A new emphasis on larger-scale biomarker, genetic, and epigenetic research focused on the molecular targets of mental disorders has been recently advocated.212 In addition, the integration of cognitive and behavioral modification of circuit-wide neuroplasticity (ie, computer-based training to enhance executive function) may prove to be an effective adjunct-treatment approach for addiction, particularly when combined with cognitive enhancers.198,213–216 Furthermore, in order to be effective, all pharmacological or biologically based treatments for addiction need to be integrated into other established forms of addiction rehabilitation, such as cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities.
- ^ Hammer R, Dingel M, Ostergren J, Partridge B, McCormick J, Koenig BA (1 July 2013). "Addiction: Current Criticism of the Brain Disease Paradigm". AJOB Neuroscience. 4 (3): 27–32. doi:10.1080/21507740.2013.796328. PMC 3969751. PMID 24693488.
- ^ Heather N, Best D, Kawalek A, Field M, Lewis M, Rotgers F, Wiers RW, Heim D (4 July 2018). "Challenging the brain disease model of addiction: European launch of the addiction theory network". Addiction Research & Theory. 26 (4): 249–255. doi:10.1080/16066359.2017.1399659.
- ^ Heather N (1 April 2017). "Q: Is Addiction a Brain Disease or a Moral Failing? A: Neither". Neuroethics. 10 (1): 115–124. doi:10.1007/s12152-016-9289-0. PMC 5486515. PMID 28725283.
- ^ Satel S, Lilienfeld SO (2014). "Addiction and the brain-disease fallacy". Frontiers in Psychiatry. 4: 141. doi:10.3389/fpsyt.2013.00141. PMC 3939769. PMID 24624096.
- ^ Peele S (December 2016). "People Control Their Addictions: No matter how much the "chronic" brain disease model of addiction indicates otherwise, we know that people can quit addictions - with special reference to harm reduction and mindfulness". Addictive Behaviors Reports. 4: 97–101. doi:10.1016/j.abrep.2016.05.003. PMC 5836519. PMID 29511729.
- ^ Henden E (2017). "Addiction, Compulsion, and Weakness of the Will: A Dual-Process Perspective.". In Heather N, Gabriel S (eds.). Addiction and Choice: Rethinking the Relationship. Oxford, UK: Oxford University Press. pp. 116–132.
- ^ a b c d e f g h i j Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. ...
Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction. - ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.
Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers" - ^ a b c d e f Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID 23020045.
For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
- ^ a b c d e f g h i j k l m Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
- ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 1: Basic Principles of Neuropharmacology". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 4. ISBN 978-0-07-148127-4.
Drug abuse and addiction exact an astoundingly high financial and human toll on society through direct adverse effects, such as lung cancer and hepatic cirrhosis, and indirect adverse effects –for example, accidents and AIDS – on health and productivity.
- ^ a b c d Merikangas KR, McClair VL (June 2012). "Epidemiology of Substance Use Disorders". Hum. Genet. 131 (6): 779–89. doi:10.1007/s00439-012-1168-0. PMC 4408274. PMID 22543841.
- ^ a b c d e f g "American Board of Medical Specialties recognizes the new subspecialty of addiction medicine" (PDF). American Board of Addiction Medicine. 14 March 2016. Retrieved 3 April 2016.
Sixteen percent of the non-institutionalized U.S. population age 12 and over – more than 40 million Americans – meets medical criteria for addiction involving nicotine, alcohol or other drugs. This is more than the number of Americans with cancer, diabetes or heart conditions. In 2014, 22.5 million people in the United States needed treatment for addiction involving alcohol or drugs other than nicotine, but only 11.6 percent received any form of inpatient, residential, or outpatient treatment. Of those who do receive treatment, few receive evidence-based care. (There is no information available on how many individuals receive treatment for addiction involving nicotine.)
Risky substance use and untreated addiction account for one-third of inpatient hospital costs and 20 percent of all deaths in the United States each year, and cause or contribute to more than 100 other conditions requiring medical care, as well as vehicular crashes, other fatal and non-fatal injuries, overdose deaths, suicides, homicides, domestic discord, the highest incarceration rate in the world and many other costly social consequences. The economic cost to society is greater than the cost of diabetes and all cancers combined. Despite these startling statistics on the prevalence and costs of addiction, few physicians have been trained to prevent or treat it. - ^ "Economic consequences of drug abuse" (PDF). International Narcotics Control Board Report: 2013 (PDF). United Nations – International Narcotics Control Board. 2013. ISBN 978-92-1-148274-4. Retrieved 28 September 2018.
- ^ Morse RM, Flavin DK (August 1992). "The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism". JAMA. 268 (8): 1012–14. doi:10.1001/jama.1992.03490080086030. PMID 1501306.
- ^ Marlatt GA, Baer JS, Donovan DM, Kivlahan DR (1988). "Addictive behaviors: etiology and treatment". Annu Rev Psychol. 39: 223–52. doi:10.1146/annurev.ps.39.020188.001255. PMID 3278676.
- ^ Gansner ME (12 September 2019). "Gaming Addiction in ICD-11: Issues and Implications". Psychiatric Times. Retrieved 3 March 2020.
- ^ a b American Psychiatric Association (2013). "Substance-Related and Addictive Disorders" (PDF). American Psychiatric Publishing. pp. 1–2. Archived from the original (PDF) on 15 August 2015. Retrieved 10 July 2015.
Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance.
- ^ a b Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 978-0-07-182770-6.
The official diagnosis of drug addiction by the Diagnostic and Statistic Manual of Mental Disorders (2013), which uses the term substance use disorder, is flawed. Criteria used to make the diagnosis of substance use disorders include tolerance and somatic dependence/withdrawal, even though these processes are not integral to addiction as noted. It is ironic and unfortunate that the manual still avoids use of the term addiction as an official diagnosis, even though addiction provides the best description of the clinical syndrome.
- ^ Washburn DA (2016). "The Stroop effect at 80: The competition between stimulus control and cognitive control". J Exp Anal Behav. 105 (1): 3–13. doi:10.1002/jeab.194. PMID 26781048.
Today, arguably more than at any time in history, the constructs of attention, executive functioning, and cognitive control seem to be pervasive and preeminent in research and theory. Even within the cognitive framework, however, there has long been an understanding that behavior is multiply determined, and that many responses are relatively automatic, unattended, contention-scheduled, and habitual. Indeed, the cognitive flexibility, response inhibition, and self-regulation that appear to be hallmarks of cognitive control are noteworthy only in contrast to responses that are relatively rigid, associative, and involuntary.
- ^ Diamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–68. doi:10.1146/annurev-psych-113011-143750. PMC 4084861. PMID 23020641.
Core EFs are inhibition [response inhibition (self-control – resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ...
EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one's attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what's more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn’t make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice. ... The subthalamic nucleus appears to play a critical role in preventing such impulsive or premature responding (Frank 2006). - ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–21. ISBN 978-0-07-148127-4.
• Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
• Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...
These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called "top-down" control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. Subjects with ADHD exhibit less activation of the medial prefrontal cortex than healthy controls even when they succeed in such tasks and utilize different circuits. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention. - ^ a b c d Karila L, Wéry A, Weinstein A, Cottencin O, Petit A, Reynaud M, Billieux J (2014). "Sexual addiction or hypersexual disorder: different terms for the same problem? A review of the literature". Curr. Pharm. Des. 20 (25): 4012–20. doi:10.2174/13816128113199990619. PMID 24001295.
Sexual addiction, which is also known as hypersexual disorder, has largely been ignored by psychiatrists, even though the condition causes serious psychosocial problems for many people. A lack of empirical evidence on sexual addiction is the result of the disease's complete absence from versions of the Diagnostic and Statistical Manual of Mental Disorders. ... Existing prevalence rates of sexual addiction-related disorders range from 3% to 6%. Sexual addiction/hypersexual disorder is used as an umbrella construct to encompass various types of problematic behaviors, including excessive masturbation, cybersex, pornography use, sexual behavior with consenting adults, telephone sex, strip club visitation, and other behaviors. The adverse consequences of sexual addiction are similar to the consequences of other addictive disorders. Addictive, somatic and psychiatric disorders coexist with sexual addiction. In recent years, research on sexual addiction has proliferated, and screening instruments have increasingly been developed to diagnose or quantify sexual addiction disorders. In our systematic review of the existing measures, 22 questionnaires were identified. As with other behavioral addictions, the appropriate treatment of sexual addiction should combine pharmacological and psychological approaches.
- ^ a b c d e Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.
Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
- ^ a b c d e Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–64. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. S2CID 25317397.
- ^ Nehlig A (2004). Coffee, tea, chocolate, and the brain. Boca Raton: CRC Press. pp. 203–218. ISBN 9780429211928.
- ^ Meule A, Gearhardt AN (September 2014). "Food addiction in the light of DSM-5". Nutrients. 6 (9): 3653–71. doi:10.3390/nu6093653. PMC 4179181. PMID 25230209.
- ^ a b c Grant JE, Potenza MN, Weinstein A, Gorelick DA (September 2010). "Introduction to behavioral addictions". Am. J. Drug Alcohol Abuse. 36 (5): 233–241. doi:10.3109/00952990.2010.491884. PMC 3164585. PMID 20560821.
Naltrexone, a mu-opioid receptor antagonist approved by the US Food and Drug Administration for the treatment of alcoholism and opioid dependence, has shown efficacy in controlled clinical trials for the treatment of pathological gambling and kleptomania (76–79), and promise in uncontrolled studies of compulsive buying (80), compulsive sexual behavior (81), internet addiction (82), and pathologic skin picking (83). ... Topiramate, an anti-convulsant which blocks the AMPA subtype of glutamate receptor (among other actions), has shown promise in open-label studies of pathological gambling, compulsive buying, and compulsive skin picking (85), as well as efficacy in reducing alcohol (86), cigarette (87), and cocaine (88) use. N-acetyl cysteine, an amino acid that restores extracellular glutamate concentration in the nucleus accumbens, reduced gambling urges and behavior in one study of pathological gamblers (89), and reduces cocaine craving (90) and cocaine use (91) in cocaine addicts. These studies suggest that glutamatergic modulation of dopaminergic tone in the nucleus accumbens may be a mechanism common to behavioral addiction and substance use disorders (92).
- ^ a b c d e f g h i j k l m n o p Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159.
However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment also plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ...
The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring. - ^ Mayfield RD, Harris RA,1, Schuckit MA (May 2008) "Genetic factors influencing alcohol dependence" PMID 18362899
- ^ a b Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ (May 1994). "A twin-family study of alcoholism in women". Am J Psychiatry. 151 (5): 707–15. doi:10.1176/ajp.151.5.707. PMID 8166312.
- ^ Clarke TK, Crist RC, Kampman KM, Dackis CA, Pettinati HM, O'Brien CP, Oslin DW, Ferraro TN, Lohoff FW, Berrettini WH (2013). "Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine". Neuroscience Letters. 542: 71–75. doi:10.1016/j.neulet.2013.02.018. PMC 3640707. PMID 23454283.
- ^ Hall FS, Drgonova J, Jain S, Uhl GR (December 2013). "Implications of genome wide association studies for addiction: are our a priori assumptions all wrong?". Pharmacology & Therapeutics. 140 (3): 267–79. doi:10.1016/j.pharmthera.2013.07.006. PMC 3797854. PMID 23872493.
- ^ Crowe, J.R. "Genetics of alcoholism". Alcohol Health and Research World: 1–11. Retrieved 13 December 2017.
- ^ Melemis SM. "The Genetics of Addiction – Is Addiction a Disease?". I Want to Change My Life. Retrieved 17 September 2018.
- ^ "Overdose Death Rates". National Institute on Drug Abuse. 9 August 2018. Retrieved 17 September 2018.
- ^ "Overdose Deaths Accelerating During Covid-19". Centers For Disease Control Prevention. 18 December 2020. Retrieved 10 February 2021.
- ^ Yang, Haiyang; Ma, Jingjing (1 August 2021). "How the COVID-19 pandemic impacts tobacco addiction: Changes in smoking behavior and associations with well-being". Addictive Behaviors. 119: 106917. doi:10.1016/j.addbeh.2021.106917. ISSN 0306-4603. PMID 33862579. S2CID 233278782.
- ^ a b "What are risk factors and protective factors?". National Institute on Drug Abuse. Retrieved 13 December 2017.
- ^ "Understanding Drug Use and Addiction". www.drugabuse.gov. National Institute on Drug Abuse. Retrieved 29 May 2020.
- ^ Lewis M (October 2018). Longo DL (ed.). "Brain Change in Addiction as Learning, Not Disease". The New England Journal of Medicine. 379 (16): 1551–1560. doi:10.1056/NEJMra1602872. PMID 30332573.
Addictive activities are determined neither solely by brain changes nor solely by social conditions ... the narrowing seen in addiction takes place within the behavioral repertoire, the social surround, and the brain — all at the same time.
- ^ a b "Adverse Childhood Experiences". samhsa.gov. Rockville, Maryland, United States: Substance Abuse and Mental Health Services Administration. Archived from the original on 9 October 2016. Retrieved 26 September 2016.
- ^ a b Enoch, Mary (2011). "The role of early life stress as a predictor for alcohol and drug dependence". Psychopharmacology. 214 (1): 17–31. doi:10.1007/s00213-010-1916-6. PMC 3005022. PMID 20596857.
- ^ "Environmental Risk Factors". learn.genetics.utah.edu. Archived from the original on 17 September 2018. Retrieved 17 September 2018.
- ^ Spear LP (June 2000). "The adolescent brain and age-related behavioral manifestations". Neuroscience and Biobehavioral Reviews. 24 (4): 417–63. CiteSeerX 10.1.1.461.3295. doi:10.1016/s0149-7634(00)00014-2. PMID 10817843. S2CID 14686245.
- ^ Hammond CJ, Mayes LC, Potenza MN (April 2014). "Neurobiology of adolescent substance use and addictive behaviors: treatment implications". Adolescent Medicine. 25 (1): 15–32. PMC 4446977. PMID 25022184.
- ^ Catalano RF, Hawkins JD, Wells EA, Miller J, Brewer D (1990). "Evaluation of the effectiveness of adolescent drug abuse treatment, assessment of risks for relapse, and promising approaches for relapse prevention". The International Journal of the Addictions. 25 (9A–10A): 1085–140. doi:10.3109/10826089109081039. PMID 2131328.
- ^ Perepletchikova F, Krystal JH, Kaufman J (November 2008). "Practitioner review: adolescent alcohol use disorders: assessment and treatment issues". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 49 (11): 1131–54. doi:10.1111/j.1469-7610.2008.01934.x. PMC 4113213. PMID 19017028.
- ^ "Age and Substance Abuse – Alcohol Rehab".
- ^ a b c "Nationwide Trends". National Institute on Drug Abuse. June 2015. Retrieved 15 December 2017.
- ^ a b "Addiction Statistics – Facts on Drug and Alcohol Addiction". AddictionCenter. Retrieved 17 September 2018.
- ^ SAMHSA. "Risk and Protective Factors". Substance Abuse and Mental Health Administration. Archived from the original on 8 December 2016. Retrieved 19 December 2016.
- ^ "Infographic – Risk Factors of Addiction | Recovery Research Institute". www.recoveryanswers.org. Archived from the original on 17 December 2016. Retrieved 19 December 2016.
- ^ "Drug addiction Risk factors – Mayo Clinic". www.mayoclinic.org. Retrieved 19 December 2016.
- ^ "The Connection Between Mental Illness and Substance Abuse | Dual Diagnosis". Dual Diagnosis. Retrieved 17 September 2018.
- ^ a b c Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, Arias-Carrión O, Machado S, Hou G, So KF (2015). "Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism". Mol. Neurobiol. 53 (9): 6367–76. doi:10.1007/s12035-015-9526-2. hdl:10400.22/7331. PMID 26572641. S2CID 25694221.
- ^ a b "Drug abuse liability". www.cambridgecognition.com. Retrieved 9 March 2021.
- ^ Abuse, National Institute on Drug (20 August 2020). "Commonly Used Drugs Charts". National Institute on Drug Abuse. Retrieved 9 March 2021.
- ^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. PMC 2834246. PMID 19877494.
[Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events - ^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950.
Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
- ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
- ^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
Figure 1
- ^ a b c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression - ^ a b c d Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970.
The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
- ^ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.
Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
- ^ a b Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.
- ^ Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.
- ^ Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014.
- ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. USA. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.
- ^ a b c d e f g h Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695.
Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. - ^ a b c d Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.
It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
- ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–85. ISBN 978-0-07-148127-4.
- ^ Salamone JD (1992). "Complex motor and sensorimotor functions of striatal and accumbens dopamine: involvement in instrumental behavior processes". Psychopharmacology. 107 (2–3): 160–74. doi:10.1007/bf02245133. PMID 1615120. S2CID 30545845.
- ^ Kauer JA, Malenka RC (November 2007). "Synaptic plasticity and addiction". Nature Reviews. Neuroscience. 8 (11): 844–58. doi:10.1038/nrn2234. PMID 17948030. S2CID 38811195.
- ^ Witten IB, Lin SC, Brodsky M, Prakash R, Diester I, Anikeeva P, et al. (December 2010). "Cholinergic interneurons control local circuit activity and cocaine conditioning". Science. 330 (6011): 1677–81. Bibcode:2010Sci...330.1677W. doi:10.1126/science.1193771. PMC 3142356. PMID 21164015.
- ^ a b Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11042–46. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.
Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal ... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well.
- ^ a b Jones S, Bonci A (2005). "Synaptic plasticity and drug addiction". Current Opinion in Pharmacology. 5 (1): 20–25. doi:10.1016/j.coph.2004.08.011. PMID 15661621.
- ^ a b Eisch AJ, Harburg GC (2006). "Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology". Hippocampus. 16 (3): 271–86. doi:10.1002/hipo.20161. PMID 16411230. S2CID 23667629.
- ^ Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 596. ISBN 978-0-443-07145-4.
- ^ Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007). "Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens". J. Neurosci. 27 (30): 7921–28. doi:10.1523/JNEUROSCI.1859-07.2007. PMC 6672735. PMID 17652583.
- ^ a b Kalivas PW, Volkow ND (August 2005). "The neural basis of addiction: a pathology of motivation and choice". The American Journal of Psychiatry. 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761.
- ^ a b Floresco SB, Ghods-Sharifi S (February 2007). "Amygdala-prefrontal cortical circuitry regulates effort-based decision making". Cerebral Cortex. 17 (2): 251–60. CiteSeerX 10.1.1.335.4681. doi:10.1093/cercor/bhj143. PMID 16495432.
- ^ Perry CJ, Zbukvic I, Kim JH, Lawrence AJ (October 2014). "Role of cues and contexts on drug-seeking behaviour". British Journal of Pharmacology. 171 (20): 4636–72. doi:10.1111/bph.12735. PMC 4209936. PMID 24749941.
- ^ a b c Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007). "Dopamine in drug abuse and addiction: results of imaging studies and treatment implications". Arch. Neurol. 64 (11): 1575–79. doi:10.1001/archneur.64.11.1575. PMID 17998440.
- ^ "Drugs, Brains, and Behavior: The Science of Addiction". National Institute on Drug Abuse.
- ^ "Understanding Drug Abuse and Addiction". National Institute on Drug Abuse. November 2012. Archived from the original on 23 August 2011. Retrieved 12 February 2015.
- ^ a b c Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.
Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch – from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure – cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3 - ^ a b c d e f Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–43. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042.
Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in addicts.
Cue-triggered ‘wanting’ for the UCS
A brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.
Cue as attractive motivational magnets
When a Pavlovian CS+ is attributed with incentive salience it not only triggers ‘wanting’ for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed ‘wanting’ – CS-triggered pulses of intensified ‘wanting’ for the UCS reward; and (ii) CS-directed ‘wanting’ – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet. - ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–48, 366–67, 375–76. ISBN 978-0-07-148127-4.
VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards. ...
The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner. ...
The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc. ... If motivational drive is described in terms of wanting, and hedonic evaluation in terms of liking, it appears that wanting can be dissociated from liking and that dopamine may influence these phenomena differently. Differences between wanting and liking are confirmed in reports by human addicts, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance. - ^ a b c d Edwards S (2016). "Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder". Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs. Prog. Brain Res. Progress in Brain Research. 223. pp. 63–76. doi:10.1016/bs.pbr.2015.07.005. ISBN 978-0-444-63545-7. PMID 26806771.
An important dimension of reinforcement highly relevant to the addiction process (and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary reinforcers (in many cases also considered conditioned reinforcers) likely drive the majority of reinforcement processes in humans. In the specific case of drug addition, cues and contexts that are intimately and repeatedly associated with drug use will often themselves become reinforcing ... A fundamental piece of Robinson and Berridge's incentive-sensitization theory of addiction posits that the incentive value or attractive nature of such secondary reinforcement processes, in addition to the primary reinforcers themselves, may persist and even become sensitized over time in league with the development of drug addiction (Robinson and Berridge, 1993).
- ^ a b Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–64. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633.
- ^ Traynor J (March 2012). "μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology". Drug Alcohol Depend. 121 (3): 173–80. doi:10.1016/j.drugalcdep.2011.10.027. PMC 3288798. PMID 22129844.
- ^ a b c d e f g h Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–21. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626.
Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure
- ^ Petry NM, Rehbein F, Gentile DA, Lemmens JS, Rumpf HJ, Mößle T, Bischof G, Tao R, Fung DS, Borges G, Auriacombe M, González Ibáñez A, Tam P, O'Brien CP (September 2014). "An international consensus for assessing internet gaming disorder using the new DSM-5 approach". Addiction. 109 (9): 1399–406. doi:10.1111/add.12457. PMID 24456155.
- ^ Torres G, Horowitz JM (1999). "Drugs of abuse and brain gene expression". Psychosom Med. 61 (5): 630–50. CiteSeerX 10.1.1.326.4903. doi:10.1097/00006842-199909000-00007. PMID 10511013.
- ^ Insel T. "Transforming Diagnosis". National Institute of Mental Health. Retrieved 17 June 2015.
- ^ Hampton WH, Hanik I, Olson IR (2019). "Substance Abuse and White Matter: Findings, Limitations, and Future of Diffusion Tensor Imaging Research". Drug and Alcohol Dependence. 197 (4): 288–298. doi:10.1016/j.drugalcdep.2019.02.005. PMC 6440853. PMID 30875650.
Despite this progress, our ability to predict, diagnose, and track addiction in humans based on brain images has been relatively limited. The difficulty elucidating such outcomes may be partly due to a relative dearth of research considering neural white matter, which constitutes over half of human brain volume and plays a vital role in governing communication between cortical areas (Fields, 2008). Diffusion mag- netic resonance imaging has emerged as a method to non-invasively examine white matter in the human brain and relate such connectivity to substance abuse and addictive behaviors (Suckling and Nestor, 2017)
- ^ Walter M, Dürsteler KM, Petitjean SA, Wiesbeck GA, Euler S, Sollberger D, Lang UE, Vogel M (2015). "[Psychosocial Treatment of Addictive Disorders – An Overview of Psychotherapeutic Options and their Efficacy]". Fortschr Neurol Psychiatr (in German). 83 (4): 201–10. doi:10.1055/s-0034-1399338. PMID 25893493.
Addictive disorders are chronic relapsing conditions marked by compulsive and often uncontrolled use of psychotropic substances or stimuli. In this review, we present and discuss the current specific psychosocial interventions for addictive disorders and their effectiveness. In particular cognitive behavioral therapy, motivational interviewing, relapse prevention, the community reinforcement approach, and contingency management were found to be effective. For these psychotherapeutic treatments, mostly moderate effect sizes have been found. Their effectiveness seems to be highest in cannabis dependence. Empirical evidence for dependence on "hard" drugs is largest for contingency management, while for alcohol dependence motivational interviewing and the community reinforcement approach show the largest effect sizes. Presumably, combinations of different approaches as well as online interventions will bring further progress in the psychosocial treatment of addictive disorders in the future.
- ^ Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113. PMID 26903885.
Environmental Enrichment ...
In humans, non-drug rewards delivered in a contingency management (CM) format successfully reduced drug dependence ... In general, CM programs promote drug abstinence through a combination of positive reinforcement for drug-free urine samples. For instance, voucher-based reinforcement therapy in which medication compliance, therapy session attendance, and negative drug screenings reinforced with vouchers to local business (e.g., movie theater, restaurants, etc.) directly reinforces drug abstinence, provides competing reinforcers, enriches the environment, and it is a robust treatment across a broad range of abused drugs (189). ...
Physical Exercise
There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... However, a RTC study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon. [emphasis added] - ^ a b c d Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439.
[exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
- ^ a b Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am J Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC 4831948. PMID 25397661.
The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
- ^ a b Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Front. Neuroendocrinol. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC 4712120. PMID 26182835.
Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. ... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed.
- ^ Sachdeva A, Choudhary M, Chandra M. (Sep 2015) "Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond." PMID: 26500991
- ^ Soyka M, Roesner S (December 2006). "New pharmacological approaches for the treatment of alcoholism". Expert Opinion on Pharmacotherapy. 7 (17): 2341–53. doi:10.1517/14656566.7.17.2341. PMID 17109610. S2CID 2587029.
- ^ Pettinati HM, Rabinowitz AR (October 2006). "Choosing the right medication for the treatment of alcoholism". Current Psychiatry Reports. 8 (5): 383–88. doi:10.1007/s11920-006-0040-0. PMID 16968619. S2CID 39826013.
- ^ Bouza C, Angeles M, Magro A, Muñoz A, Amate JM (July 2004). "Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review". Addiction. 99 (7): 811–28. doi:10.1111/j.1360-0443.2004.00763.x. PMID 15200577.
- ^ Williams SH (November 2005). "Medications for treating alcohol dependence". American Family Physician. 72 (9): 1775–80. PMID 16300039.
- ^ Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M (December 2010). Srisurapanont M (ed.). "Opioid antagonists for alcohol dependence". The Cochrane Database of Systematic Reviews (12): CD001867. doi:10.1002/14651858.CD001867.pub2. PMID 21154349.
- ^ "Drug Addiction Treatment & Admissions Overview". River Oaks. Retrieved 18 November 2020.
- ^ Sofuoglu M, Sugarman DE, Carroll KM (April 2010). "Cognitive function as an emerging treatment target for marijuana addiction". Exp Clin Psychopharmacol. 18 (2): 109–19. doi:10.1037/a0019295. PMC 2909584. PMID 20384422.
Cannabis is the most widely used illicit substance in the world, and demand for effective treatment is increasing. However, abstinence rates following behavioral therapies have been modest, and there are no effective pharmacotherapies for the treatment of cannabis addiction.
- ^ Fratta W, Fattore L (August 2013). "Molecular mechanisms of cannabinoid addiction". Curr. Opin. Neurobiol. 23 (4): 487–92. doi:10.1016/j.conb.2013.02.002. PMID 23490548. S2CID 40849553.
14. Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ: b-Arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region dependent manner. Biol Psychiatry 2012, 71:714–24.
A pioneering study revealing both positive and negative modulatory effects of beta-arrestin2 on THC tolerance. By demonstrating that tolerance to antinociception is reduced whereas tolerance to catalepsy is enhanced in beta-arrestin2 knockout mice, authors suggest that development of cannabinoid agonists that minimize interactions between CB1Rs and beta-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression, and be therapeutically beneficial. - ^ a b Garwood CL, Potts LA (2007). "Emerging pharmacotherapies for smoking cessation". Am J Health Syst Pharm. 64 (16): 1693–98. doi:10.2146/ajhp060427. PMID 17687057.
- ^ a b Crooks PA, Bardo MT, Dwoskin LP (2014). "Nicotinic receptor antagonists as treatments for nicotine abuse". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv. Pharmacol. Advances in Pharmacology. 69. pp. 513–51. doi:10.1016/B978-0-12-420118-7.00013-5. ISBN 978-0-12-420118-7. PMC 4110698. PMID 24484986.
- ^ Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (November 2000). "A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence". The New England Journal of Medicine. 343 (18): 1290–7. doi:10.1056/NEJM200011023431802. PMID 11058673.
- ^ Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al. (March 2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health Technology Assessment. 11 (9): 1–171, iii–iv. doi:10.3310/hta11090. PMID 17313907.
- ^ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A (December 2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction. 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID 17156174.
- ^ Qin B (1998). "Advances in dihydroetorphine: From analgesia to detoxification". Drug Development Research. 39 (2): 131–34. doi:10.1002/(SICI)1098-2299(199610)39:2<131::AID-DDR3>3.0.CO;2-Q. Link
- ^ Metrebian N, Shanahan W, Wells B, Stimson GV (June 1998). "Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions". The Medical Journal of Australia. 168 (12): 596–600. doi:10.5694/j.1326-5377.1998.tb141444.x. PMID 9673620. S2CID 43302721.
- ^ Metrebian N, Mott J, Carnwath Z, Carnwath T, Stimson GV, Sell L (2007). "Pathways into receiving a prescription for diamorphine (heroin) for the treatment of opiate dependence in the United kingdom". European Addiction Research. 13 (3): 144–7. doi:10.1159/000101550. PMID 17570910. S2CID 7397513.
- ^ Kenna GA, Nielsen DM, Mello P, Schiesl A, Swift RM (2007). "Pharmacotherapy of dual substance abuse and dependence". CNS Drugs. 21 (3): 213–37. doi:10.2165/00023210-200721030-00003. PMID 17338593. S2CID 25979050.
- ^ Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, Gossop M (May 2003). "Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study". BMJ (Clinical Research Ed.). 326 (7396): 959–60. doi:10.1136/bmj.326.7396.959. PMC 153851. PMID 12727768.
- ^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research". Expert Rev Clin Pharmacol. 7 (3): 363–74. doi:10.1586/17512433.2014.909283. PMC 4017926. PMID 24716825.
Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
- ^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9 (9): CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457.
To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy
- ^ Forray A, Sofuoglu M (February 2014). "Future pharmacological treatments for substance use disorders". Br. J. Clin. Pharmacol. 77 (2): 382–400. doi:10.1111/j.1365-2125.2012.04474.x. PMC 4014020. PMID 23039267.
- ^ a b Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction" – The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC 4724540. PMID 26644139.
When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
- ^ a b Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–52. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759.
Taken together, the data reviewed here strongly support that TAAR1 is implicated in the functional regulation of monoaminergic systems, especially dopaminergic system, and that TAAR1 serves as a homeostatic "brake" system that is involved in the modulation of dopaminergic activity. Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. ... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010).
- ^ a b Liu JF, Li JX (December 2018). "Drug addiction: a curable mental disorder?". Acta Pharmacologica Sinica. 39 (12): 1823–1829. doi:10.1038/s41401-018-0180-x. PMC 6289334. PMID 30382181.
- ^ a b c Zalewska-Kaszubska J (November 2015). "Is immunotherapy an opportunity for effective treatment of drug addiction?". Vaccine. 33 (48): 6545–51. doi:10.1016/j.vaccine.2015.09.079. PMID 26432911.
- ^ Laudenbach M, Baruffaldi F, Vervacke JS, Distefano MD, Titcombe PJ, Mueller DL, Tubo NJ, Griffith TS, Pravetoni M (June 2015). "The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse". J. Immunol. 194 (12): 5926–36. doi:10.4049/jimmunol.1500385. PMC 4458396. PMID 25972483.
Translation of therapeutic vaccines for addiction, cancer, or other chronic noncommunicable diseases has been slow because only a small subset of immunized subjects achieved effective Ab levels.
- ^ Painter A. (2019) "Researchers working to develop vaccines to fight opioid addiction" Vtnews.vt.edu
- ^ a b c d Cao DN, Shi JJ, Hao W, Wu N, Li J (March 2016). "Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction". Eur. J. Pharmacol. 780: 129–35. doi:10.1016/j.ejphar.2016.03.040. PMID 27018393.
- ^ a b Moeller SJ, London ED, Northoff G (February 2016). "Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity". Neurosci Biobehav Rev. 61: 35–52. doi:10.1016/j.neubiorev.2015.11.010. PMC 4731270. PMID 26657968.
- ^ Agabio R, Colombo G (April 2015). "[GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators]". Psychiatr. Pol. (in Polish). 49 (2): 215–23. doi:10.12740/PP/33911. PMID 26093587.
- ^ Filip M, Frankowska M, Sadakierska-Chudy A, Suder A, Szumiec L, Mierzejewski P, Bienkowski P, Przegaliński E, Cryan JF (January 2015). "GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators". Neuropharmacology. 88: 36–47. doi:10.1016/j.neuropharm.2014.06.016. PMID 24971600. S2CID 207229988.
- ^ a b McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 27453897.
Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.
- ^ a b Primary references involving sodium butyrate:
• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–40. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113.While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression3 or decreased acquisition of behavioral adaptations to drug5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.
• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–89. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144.Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762.treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
- ^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–19. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036.
Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.
- ^ Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.
- ^ "Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol".
- ^ "Gene Transfer Therapy for Cocaine Addiction Passes Tests in Animals". National Institute on Drug Abuse. 14 January 2016.
- ^ Murthy V, Gao Y, Geng L, LeBrasseur NK, White TA, Parks RJ, Brimijoin S (2014). "Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice". Vaccine. 32 (33): 4155–62. doi:10.1016/j.vaccine.2014.05.067. PMC 4077905. PMID 24892251.
- ^ "Using Adeno-Associated Virus (AAV) Mediated Sustained Expression of an Anti-methamphetamine Antibody Fragment to Alter Methamphetamine Disposition in Mice" (PDF). Archived from the original (PDF) on 3 March 2018. Retrieved 25 June 2017.
- ^ "ATTC – Addiction Science Made Easy". www.attcnetwork.org. Archived from the original on 27 September 2018. Retrieved 25 June 2017.
- ^ Chen CC, Yin SJ. (Oct 2008) "Alcohol abuse and related factors in Asia". PMID: 19012127
- ^ Mak KK, Lai CM, Watanabe H. (Nov 2014) "Epidemiology of internet behaviors and addiction among adolescents in six Asian countries". PMID: 25405785
- ^ Slade T, Johnston A, Teesson M, Whiteford H, Burgess P, Pirkis J, Saw S (May 2009). "The Mental Health of Australians 2: Substance Use Disorders in Australia" (PDF). Department of Health and Ageing, Canberra.
- ^ Peacock A, Leung J, Larney S. (Oct 2018) "Global statistics on alcohol, tobacco and illicit drug use: 2017 status report." PMID: 29749059
- ^ Manubay JM, Muchow C, Sullivan MA (March 2011). "Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics". Primary Care. 38 (1): 71–90. doi:10.1016/j.pop.2010.11.006. PMC 3328297. PMID 21356422.
- ^ a b c d Volkow N (31 March 2016). "A Major Step Forward for Addiction Medicine". National Institute on Drug Abuse. National Institutes of Health. Retrieved 3 April 2016.
Only about 10 percent of the 21 million Americans who meet the need for care for an alcohol or drug use disorder receive any form of treatment, and much of the treatment available does not meet standards for evidence-based care. There are many attitudinal and systemic reasons for this treatment gap, including stigma against treating people with addictions and institutional barriers to providing or funding addiction treatment. ... A major milestone was reached on March 14, 2016, when the American Board of Medical Specialties (ABMS) formally announced recognition of the field of Addiction Medicine as a medical subspecialty. ... In a statement issued to mark this milestone, ABAM President Robert J. Sokol summed up its significance: 'This landmark event, more than any other, recognizes addiction as a preventable and treatable disease, helping to shed the stigma that has long plagued it. It sends a strong message to the public that American medicine is committed to providing expert care for this disease and services designed to prevent the risky substance use that precedes it.'
- ^ Gramlich J (26 October 2017). "Nearly half of Americans have a family member or close friend who's been addicted to drugs". Pew Research Center. Retrieved 14 January 2018.
- ^ "We were addicted to their pill, but they were addicted to the money". The Washington Post. Retrieved 22 July 2019.
- ^ World Drug Report 2012 (PDF). United Nations Office on Drugs and Crime. United Nations. June 2012. ISBN 978-92-1-148267-6.
- ^ Pacurucu-Castillo SF, Ordóñez-Mancheno JM, Hernández-Cruz A, Alarcón RD (April 2019). "World opioid and substance use epidemic: a Latin American perspective". Psychiatric Research and Clinical Practice. 1 (1): 32–8. doi:10.1176/appi.prcp.20180009.
- ^ Fehrman E, Egan V, Gorban AN, Levesley J, Mirkes EM, Muhammad AK (2019). Personality Traits and Drug Consumption. A Story Told by Data. Springer, Cham. arXiv:2001.06520. doi:10.1007/978-3-030-10442-9. ISBN 978-3-030-10441-2. S2CID 151160405.
- ^ Cheetham A, Allen NB, Yücel M, Lubman DI (August 2010). "The role of affective dysregulation in drug addiction". Clin Psychol Rev. 30 (6): 621–34. doi:10.1016/j.cpr.2010.04.005. PMID 20546986.
- ^ Franken IH, Muris P (2006). "BIS/BAS personality characteristics and college students' substance use". Personality and Individual Differences. 40 (7): 1497–503. doi:10.1016/j.paid.2005.12.005.
- ^ Genovese JE, Wallace D (December 2007). "Reward sensitivity and substance abuse in middle school and high school students". J Genet Psychol. 168 (4): 465–69. doi:10.3200/GNTP.168.4.465-469. PMID 18232522. S2CID 207640075.
- ^ Kimbrel NA, Nelson-Gray RO, Mitchell JT (April 2007). "Reinforcement sensitivity and maternal style as predictors of psychopathology". Personality and Individual Differences. 42 (6): 1139–49. doi:10.1016/j.paid.2006.06.028.
- ^ Dawe S, Loxton NJ (May 2004). "The role of impulsivity in the development of substance use and eating disorders". Neurosci Biobehav Rev. 28 (3): 343–51. doi:10.1016/j.neubiorev.2004.03.007. PMID 15225976. S2CID 24435589.
- ^ jetcopter
- ^ Online Etymology Dictionary : alcohol
- ^ Sexaholism: The Closet Addiction (article) by Niki Collins-Queen on AuthorsDen:January 29, 2005
- ^ Sexaholism: A Perspective - Sexual Addiction & Compulsivity: The Journal of Treatment & Prevention:(Sexual Addiction & Compulsivity, Volume 13, Issue 1 January 2006, pages 69 - 94)
- ^ [1](blank page?)
- ^ Culture Shock:Shopaholism (by Prachi Thanawala)
- ^ WWE: Inside WWE > News > Archive > Chris Jericho to rock Celebrity Duets:By: Jen Hunt Written: August 23, 2006
Otras lecturas
- Szalavitz M (2016). Unbroken Brain. St. Martin's Press. ISBN 978-1-250-05582-8.
enlaces externos
Classification | D
|
---|
- "The Science of Addiction: Genetics and the Brain". learn.genetics.utah.edu. Learn.Genetics – University of Utah.
- Why do our brains get addicted? – a TEDMED 2014 talk by Nora Volkow, the director of the National Institute on Drug Abuse at NIH.
- Laterality of Brain Activation for Risk Factors of Addiction
Kyoto Encyclopedia of Genes and Genomes (KEGG) signal transduction pathways:
- KEGG – human alcohol addiction
- KEGG – human amphetamine addiction
- KEGG – human cocaine addiction
- – What are different types of Drug Addiction Treatment Programs