Dopamine D1 receptors in the medial prefrontal cortex and basolateral amygdala cooperatively contribute to social defeat stress-induced augmentation of cocaine reward in mice

Abstract

Stress potentiates the rewarding effects of cocaine; however, its underlying mechanism remains unclear. Here, we investigated the role of dopaminergic transmission in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA), key brain regions implicated in addiction and stress responses, using the cocaine conditioned place preference (CPP) paradigm combined with acute social defeat (SD) stress in male mice. SD stress exposed immediately before the posttest augmented cocaine CPP, which was significantly reduced by systemic injection of SCH23390, a dopamine D₁ receptor antagonist. Fiber photometry recordings using a GRAB_DA sensor revealed SD stress-induced elevations in extracellular dopamine levels in both the mPFC and BLA. Accordingly, bilateral intra-mPFC or bilateral intra-BLA injections of SCH23390 suppressed the stress-induced augmentation of cocaine CPP. Additionally, functional disconnection, achieved via unilateral intra-mPFC SCH23390 injection combined with contralateral intra-BLA SCH23390 injection, suppressed stress-induced CPP augmentation. Moreover, unilateral intra-mPFC SCH23390 injection combined with contralateral intra-BLA injection of NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, inhibited the augmented CPP. Furthermore, selective chemogenetic silencing of glutamatergic projections from the mPFC to the BLA suppressed augmented cocaine CPP. These findings suggest that bilateral and simultaneous D₁ receptor-mediated dopaminergic inputs to the mPFC and BLA, as well as the subsequent facilitation of glutamatergic transmission from the mPFC to the BLA, play a crucial role in the SD stress-induced potentiation of the rewarding effects of cocaine.

Keywords: Basolateral amygdala; Conditioned place preference; Dopamine D(1) receptors; Medial prefrontal cortex; Social defeat stress.