Neuropeptidergic regulation of Compulsive Ethanol Seeking in C. elegans

An improved understanding of the molecular basis of alcohol seeking despite the catastrophic consequences of alcohol abuse is likely to enrich our treatments for Alcohol Use Disorders (AUD) and comorbidities. The compulsive seeking is characterized by an imbalance between the superior drive to substance and disruption in control of substance use. To model the development of compulsive engagement of alcohol seeking, we exploit two distinct behavioral programs of C. elegans in conflict, ethanol preference and avoidance of aversive stimulus, simultaneously. We demonstrate that C. elegans exhibited the recapitulation of the pivotal features of compulsive alcohol seeking in mammals, which are repeated attempts, endurance, and finally aversion-resistant ethanol seeking. We find that the neuropeptide signaling via SEB-3, CRF receptor-like GPCR, facilitates the development of ethanol preference and compels animals to seek ethanol compulsively. Furthermore, our functional genomic approach and behavioral elucidation suggest the interaction between neuropeptidergic signaling, SEB-3 and TKR-1, Neurokinin receptor orthologue, to progress compulsive ethanol seeking behavior.