Convergence of positive and negative reinforcement in fentanyl addiction

Descripción del proyecto

Comprender la base neuronal de la adicción al fentanilo

El fentanilo es un potente analgésico opioide sintético que se utiliza para tratar pacientes con dolor intenso. Más de un tercio de los usuarios se vuelven adictos en última instancia, un número que es significativamente superior del observado con psicoestimulantes, por lo que existe un mayor riesgo de muerte por sobredosis. El proyecto F-Addict, financiado con fondos europeos, tiene como objetivo desvelar la base neuronal de la adicción al fentanilo, comprender el mecanismo molecular de la modulación de circuitos y definir futuras terapias de cara a la creciente epidemia de sobredosis de opioides. Estudiará los procesos sinápticos y la actividad de la población neuronal que conducen a la adicción, usando un modelo murino de autoadministración oral de fentanilo. El proyecto definirá el papel de los refuerzos positivos y negativos en la adicción al fentanilo en contraste con los modelos de circuito actuales basados en psicoestimulantes.

Objetivo

F-Addict strives to unravel the neural circuits driving compulsion in fentanyl addiction. We ask the question how fentanyl causes fast transition from medical or recreational controlled drug use to compulsive consumption. About a third of opioid users eventually loose control, which increases the risk of death by overdose; a number that is even higher for fentanyl and definitely exceeds the transition observed with psychostimulants. The neural correlate of this difference remains elusive. We posit that repetitive withdrawal leads to strong negative reinforcement, which in conjunction with inherent positive reinforcement favors the transition to compulsion. F-Addict will uncover the synaptic processes and neuronal population activity leading to addiction in a mouse model of oral fentanyl self-administration. Much preliminary data implicate activity in the mesolimbic dopamine system and upstream subcortical regions (paraventricular thalamus/habenula/basolateral amygdala) in positive and negative reinforcement, respectively. In addition, top down control, in particular by the orbitofrontal cortex may drive compulsive drug use. The proposed project will harness advanced circuit investigations for an innovative, original perspective: how does positive and negative reinforcement in fentanyl addiction contrast with current circuit models of addiction that are based on psychostimulants? In a translational spirit, F-Addict will also examine the effects of oral substitution with methadone and buprenorphine, recognized therapies for opioid addiction. Much preliminary data provides proof of feasibility and principle. We are confident that our approach at the frontiers of modern neurosciences carries the potential for groundbreaking results to answer a timely question. Unraveling the neural basis of fentanyl addiction will enhance the molecular understanding of circuit modulation to shape future therapies facing the still growing opioid epidemic.