Caspase-dependent ablation of indirect medium spiny neurons projecting to external globus pallidus promotes compulsive ethanol-seeking and drinking behaviors

The dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors, while the dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors. In this study, we sought to investigate two pathways, direct medium spiny neuron (dMSN) and indirect medium spiny neuron (iMSN) in the two dorsal striatal subregions (DMS and DLS) in ethanol-seeking and drinking behaviors. Here, we selectively ablated iMSN ^DMS→GPe and iMSN ^DLS→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 found that partial ablation of iMSN ^DLS→GPe exhibited increased resilience to bitter-tasting ethanol solution when subjected to quinine adulterated reward in operant conditioning paradigms, suggesting compulsive-like seeking behavior. Consistently, in a separate cohort of mice, we found that the iMSN ^DLS→GPe ablated mice show higher preference and consumption of quinine adulterated ethanol solution than control mice in two-bottle choice continuous access drinking, with increasing quinine concentration and exhibit more compulsive-like behavior. On the other hand, ablation of iMSN ^DMS→GPe resulted in insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior but no change in compulsive ethanol-seeking and drinking behavior. Together, our findings demonstrate that DLS iMSN function is essential in inhibiting compulsive-like behavior.