Periodic Reporting for period 2 - F-Addict (Convergence of positive and negative reinforcement in fentanyl addiction)
Período documentado: 2021-12-01 hasta 2023-05-31
F-Addict strives to unravel the neural circuits driving compulsion in fentanyl addiction. We ask the question of how fentanyl causes a fast transition from medical or recreational controlled drug use to compulsive consumption. About a third of opioid users will eventually lose 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 fentanyl self-administration. Many preliminary data implicate activity in the mesolimbic dopamine system and upstream subcortical regions (paraventricular thalamus/habenula/amygdala) in positive and negative reinforcement, respectively. In addition, top-down control, in particular by the orbitofrontal cortex may drive compulsive drug use. F-addict will harness advanced circuit investigations for an innovative, original perspective: how does positive and negative reinforcement in fentanyl addiction integrate 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. Preliminary data provide 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.
We have started systematic investigation of the brain circuits of negative reinforcement by deleting the deletion of µORs in particular brain regions. A special focus is on nuclei with a high fraction of c-FOS positive neurons during opioid withdrawal. We have also started neurotransmitter- and calcium-imaging in freely moving animals to assess population coding in an innovative oral fentanyl self-administration model. We also have the first results from ex vivo slice physiology to integrate observations made at different levels.
The deletion of µOR in various brain regions has led to the disappearance of specific withdrawal syndrome. A model is emerging whereby opioid-related negative reinforcement starts with µOR expressing neurons in several brain regions.