DORSAL STRIATAL PDE10A GATES COCAINE SEEKING BY BIASING ACTION CONTROL AWAY FROM PERSEVERATIVE RESPONDING

A recent human cocaine addiction multi-omics study from our institute demonstrated a significant upregulation in phosphodiesterase-10A (PDE10A) in cocaine-dependent patients relative to controls, suggesting its involvement in the pathology of cocaine use disorder (CUD). PDE10A, a dual specificity cAMP/cGMP phosphodiesterase, is highly enriched in striatal medium spiny neurons, acting downstream of dopamine receptors, and thus is well-positioned to shape dopamine-dependent plasticity underlying addictive behavior. Here, we report that viral-mediated PDE10A knockdown in the dorsal striatum selectively attenuated cocaine seeking during reinstatement without altering overall cocaine intake or psychomotor activation during self-administration. Time-resolved behavioral analyses revealed that PDE10A knockdown disrupted the maintenance of drug-directed actions; following cocaine delivery, knockdown animals rapidly disengaged from the active nose-poke, shifting toward non-reinforced activity that remained coupled to locomotion. Event-locked peristimulus histograms confirmed a rapid termination of persistent active responding within seconds of reinforcement. These findings indicate a functional dissociation consistent with a model in which cocaine-associated, D1-driven behavioral vigor is preserved, whereas PDE10A knockdown biases dorsal striatal control toward D2-mediated suppression of perseverative responding. Importantly, this dissociation contrasts with the generalized motor suppression typical of global D2 receptor blockade, identifying PDE10A as a molecular target capable of uncoupling addiction-related persistence from general motor function. Together with evidence for cocaine-induced regulation of PDE10A expression across exposure stages, these results suggest that PDE10A acts as a molecular gatekeeper for maladaptive drug-seeking.