Neurobiology of Addiction

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

This project investigates the neurobiological mechanisms underlying substance use disorders, with a focus on opioid use disorder (OUD) and alcohol use disorder (AUD). Using rodent models, we studied how neuropeptide, opioid, and stress systems interact to regulate emotion, reward, and alcohol-related behaviors. We examined cellular colocalization of oxytocin, μ-opioid, and κ-opioid receptor mRNA in the central amygdala, a brain region critical for emotion regulation and addiction. Through RNAScope in situ hybridization and advanced imaging analyses, we demonstrated that a substantial proportion of central amygdala neurons co-express these receptors, suggesting cellular-level interactions that may contribute to the regulation of anxiety and substance use behaviors. These findings identify novel points of convergence between oxytocinergic and opioid systems with potential therapeutic relevance for anxiety disorders and alcohol misuse. Complementary experiments focused on the ghrelin system, which is implicated in binge drinking and alcohol reinforcement. Pharmacological manipulations revealed that growth hormone secretagogue receptors (GHSRs), rather than peripheral ghrelin release, play a critical role in driving binge-like alcohol consumption. We further explored the interplay between ghrelin and corticotropin-releasing factor (CRF) systems, showing that antagonism of central CRF1 receptors and blockade of GHSRs independently reduced alcohol drinking without additive effects. These results highlight GHSR and CRF1 receptor signaling as promising but distinct targets for AUD treatment. Finally, we reviewed evidence for the role of the dynorphin/κ-opioid receptor system in opioid withdrawal–related hyperalgesia (heightened pain sensitivity) and hyperkatifeia (negative emotional states). Pharmacological and genetic interventions targeting κ-opioid receptor signaling reduced withdrawal symptoms and addictive-like behaviors, supporting its translational potential for OUD. Together, these studies advance our understanding of how neuropeptide and opioid receptor systems converge on brain circuits governing stress, reward, and affect, and identify novel molecular targets for the treatment of alcohol and opioid use disorders.