Social defeat stress enhances the rewarding effects of cocaine through α adrenoceptors in the medial prefrontal cortex of mice.

Various stressors potentiate the rewarding effects of cocaine and contribute to cocaine cravings. However, it remains unclear whether psychosocial stress enhances the rewarding effects of cocaine. Accordingly, this study employed a cocaine-conditioned place preference (CPP) paradigm combined with social defeat (SD) exposure to investigate the effects of acute SD stress on cocaine reward in male mice. We found that SD stress immediately before the posttest significantly increased cocaine CPP, and systemic blockade of α adrenoceptors, but not β adrenoceptors, suppressed this increase. Fiber photometry recordings with GRAB sensors revealed increased noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) in test mice in response to attacks by aggressor mice during SD. Moreover, the SD stress-induced enhancement of CPP was effectively suppressed by intra-mPFC infusion of an α adrenoceptor antagonist. In vitro whole-cell recordings demonstrated that silodosin, an α, but not α or α, adrenoceptor antagonist, inhibited NA-induced depolarizing currents and facilitation of excitatory synaptic transmissions. Consistently, intra-mPFC silodosin infusion significantly suppressed the SD stress-induced CPP enhancement. Conversely, intra-mPFC infusion of α adrenoceptor agonist augmented cocaine CPP in the absence of stress exposure. Additionally, intranasal silodosin administration attenuated the SD stress-induced enhancement of CPP, and chemogenetic inhibition of mPFC excitatory neurons also suppressed the SD stress-induced CPP enhancement. Together, these findings suggest that NA stimulation of α adrenoceptors and the subsequent activation of mPFC pyramidal cells may contribute to SD stress-induced amplification of the rewarding effects of cocaine, and intranasal silodosin administration may hold therapeutic potential for mitigating stress-associated cocaine craving.