부산대학교 도서관

Various stressors potentiate the rewarding effects of cocaine, which contribute to cocaine craving. However, it remains unclear whether psychosocial stress enhances the rewarding effects of cocaine. To address this issue, we employed a cocaine-conditioned place preference (CPP) paradigm combined with social defeat (SD) exposure and investigated the effects of acute SD stress on cocaine reward in mice. We found that SD stress immediately before the posttest significantly increased cocaine CPP, and systemic blockade of α1 adrenoceptors (α1-ARs) suppressed this increase. Fiber photometry recordings with GRABNE1m sensors revealed increased noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) during SD. Moreover, the SD stress-induced enhancement of CPP was suppressed by intra-mPFC infusion of an α1-AR antagonist. In vitro whole-cell recordings showed that silodosin, an α1A-, but not α1B- or α1D-, AR antagonist, inhibited NA-induced depolarizing currents and facilitation of excitatory synaptic transmissions. Consistently, intra-mPFC silodosin infusion suppressed the SD stress-induced CPP enhancement. Additionally, chemogenetic inhibition of mPFC pyramidal cells and intranasal silodosin injection attenuated the CPP enhancement. These findings suggest that NA stimulation of α1A-ARs and the subsequent activation of mPFC pyramidal cells may contribute to SD stress-induced amplification of the rewarding effects of cocaine, and intranasal silodosin injection may hold therapeutic potential for stress-associated cocaine craving.