Stress-responsive nucleus accumbens dopamine D2 receptor-expressing neurons modulate cocaine-induced behavioral sensitization

Abstract

Although both stress and cocaine induce robust plasticity within the nucleus accumbens core (NAcc), how these distinct experiences interact at the cellular level to shape behavior remains unclear. Here, we investigated the role of NAcc dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs) in integrating stress- and drug-induced signals. D2R-MSNs showed distinct activity responses, with increased activity during restraint stress and reduced activity following repeated cocaine exposure. Using the Cre-dependent Robust Activity Marking (cRAM) system, we found that cocaine exposure suppressed the activity of the subpopulation of D2R-MSNs previously recruited by stress. Optogenetic reactivation of these stress-tagged D2R-MSNs during withdrawal attenuated the expression of cocaine-induced behavioral sensitization. Transcriptomic profiling of stress-responsive D2R-MSNs identified cholecystokinin (Cck) as a candidate associated with this neuronal manipulation. Subsequent experiments showed that cocaine exposure increased CCK expression in NAcc D2R-MSNs, whereas conditional Cck knockdown reduced the expression of behavioral sensitization. Together, these findings suggest that stress-responsive D2R-MSNs contribute to the regulation of cocaine-induced behavioral sensitization and that CCK signaling within NAcc D2R-MSNs may be involved in this process.