Chemogenetic regulation of direct and indirect pathway neurons in the dorsomedial striatum reshapes cocaine-induced conditioned place preference behaviors in mice.

The rewarding properties of cocaine generate potent and long-lasting associations with environmental cues through altering neuronal properties, underlying reinforced drug-taking and seeking behaviors. Disrupting these associations could reduce cravings and forestall relapse. The dorsomedial striatum (DMS) is implicated in reward processing and goal-directed behaviors, yet its specific role in modulating cocaine-associated contextual memory remains poorly defined. To elucidate DMS's role in cue-induced memory retrieval, multifaceted approaches were employed in male mice, including the conditioned place preference (CPP) model, behavioral assessments, c-Fos immunostaining, and chemogenetic methods. Our findings demonstrate that following a four-day conditioning period, cocaine-conditioned mice re-exposed to the CPP context exhibited increased c-Fos+ cells in the DMS, positively correlating with CPP scores. Contrary to the classical antagonistic model, chemogenetic activation of either D2 receptor- (D2-MSNs) or D1 receptor-expressing MSNs (D1-MSNs) in the DMS significantly disrupted drug-context associations and reduced acquired preference, whereas inhibition enhanced CPP behaviors. These findings demonstrate the DMS as a critical node for mediating drug-context memory retrieval, providing novel insights into the functional roles of D1- and D2-MSNs in this process. Regulating the activity of DMS neurons may be a promising strategy for reshaping maladaptive drug-context associations.