Stress-responsive Accumbal Dopamine D2 Receptor-expressing Neurons Modulate Cocaine-induced Behavioral Sensitization

ABSTRACT: Exposure to stress triggers neuroadaptations within the nucleus accumbens core (NAcc), a region central to reward processing. Cocaine exposure is also well-known to induce robust plasticity in this same area. However, it remains unclear how these two distinct signals interact at the cellular level to influence behavioral outcomes. In particular, the specific neuronal subpopulations that bridge the signals between a history of stress and subsequent cocaine-induced changes have not been fully identified. Here, we investigated the potential involvement of NAcc dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs) in mediating the interaction between stress- and cocaine-induced neural signals. We observed that D2R-MSNs exhibit differential activity patterns in response to stress and cocaine, showing increased activity following acute or chronic restraint stress and suppressed activity after repeated cocaine exposure. Using the Robust Activity Marking (RAM) system, we selectively labeled a subset of restraint stress-activated D2R-MSNs to express Channelrhodopsin-2 (ChR2). We found that c-Fos expression, a marker of neuronal activity, in these stress-labeled D2R-MSNs was significantly suppressed by subsequent cocaine exposure. Furthermore, optogenetic activation of the stress-activated D2R-MSNs during withdrawal attenuated the expression of cocaine sensitization. Through transcriptomic analysis, we identified Cholecystokinin (Cck) as a candidate molecule associated with the attenuation of cocaine sensitization observed following the optogenetic stimulation of stress-activated D2R-MSNs. We observed an increase in CCK protein expression within D2R-MSNs after cocaine sensitization, whereas optogenetic stimulation of the stress-activated D2R-MSNs was associated with its downregulation. Conditional knockdown of Cck in D2R-MSNs resulted in an attenuation of the expression of cocaine sensitization, consistent with the effects of optogenetic activation during withdrawal. Together, these findings suggest that Cck within stress-activated D2R-MSNs is a potential candidate that may contribute to the modulation of cocaine-induced behavioral sensitization.

ORGANISM(S): Mus musculus

PROVIDER: GSE334247 | GEO | 2026/09/02

REPOSITORIES: GEO