549. INDIRECT MEDIUM SPINY NEURONS IN THE DORSOLATERAL STRIATUM PROJECTING TO THE EXTERNAL GLOBUS PALLIDUS REGULATE COMPULSIVE ALCOHOL-SEEKING BEHAVIORS

Abstract Background The dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors while the dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors. Notably, activating striatal direct-pathway medium spiny neurons (dMSN) enhances reinforcement learning, whereas stimulating striatal indirect-pathway MSN (iMSN) induces avoidance behaviors and inhibits reinforcement. Although extensive research has compared the functions of DMS versus DLS or iMSN versus dMSN in reward-seeking, it remains unclear whether iMSN may exhibit distinct roles in suppressing compulsive alcohol-seeking within each specific striatal subregion. Aims & Objectives In this study, we sought to address this by selectively ablating iMSNDMS->GPe and iMSNDLS->GPe and trained mice to exhibit goal-directed and habitual reward-seeking behaviors using random ratio (RR) and random interval (RI) operant conditioning, respectively. We also aim to investigate whether circuit-specific partial ablation alters compulsive alcohol-seeking and drinking behaviors. Method To ablate the circuit in a targeted fashion, we employed a genetically engineered caspase 3, in which activation results in apoptosis. We also investigated compulsive ethanol-seeking behaviors using nose-poke operant alcohol-drinking experiments in a two-bottle choice (water versus alcohol) paradigm with or without quinine adulteration. Results Interestingly, caspase 3-mediated ablation of iMSNDMS->GPe resulted in an insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior. The ablation of iMSNDLS->GPe did not influence locomotor function in the open field test and accelerated rotor rod or anxiety-related behaviors, nor did it affect the expression of habitual or goal-directed seeking behavior during the devaluation of a random interval or random ratio operant schedule. However, when subjected to quinine adulteration, mice with iMSNDLS->GPe ablation exhibited increased compulsive alcohol-seeking behaviors in habitual and goal-directed operant conditioning paradigms. Consistently, in a separate cohort of mice, we found that the iMSNDLS->GPe ablated mice showed higher preference and consumption of alcohol than control mice in a two-bottle choice experiment, with increasing quinine concentration and exhibiting more compulsive-like behavior. The iMSNDLS->GPe ablated mice prefer more ethanol than control mice while still developing an aversion to seeking the reward. Discussion & Conclusions Altogether, our findings reveal an essential role of iMSNDLS->GPe in behavioral flexibility and inhibiting compulsive-like behavior, which may be a potential therapeutic target for alcohol and other addictive disorders. Our findings reveal a novel role of iMSNDLS->GPe in behavioral flexibility and constraining habitual reward-seeking, which may be a potential therapeutic target for alcohol use disorder and other compulsive disorders.