FG-9202

Acute restraint stress (RS) has been reported to activate the supraoptic nucleus of the hypothalamus (SON). The aim of the present study was to evaluate the role of glutamatergic neurotransmission in the SON on autonomic [mean arterial pressure (MAP), heart rate (HR), and tail cutaneous temperature], neuroendocrine (plasma levels of corticosterone, oxytocin, and vasopressin), and behavioral responses to RS.

Male Wistar rats with bilateral SON cannulas received microinjections of NMDA or non-NMDA receptor antagonists or vehicle before restraint stress, and the effects on cardiovascular, tail temperature, hormonal, and behavioral responses were evaluated RESULTS: Microinjection of DL-AP7 or NBQX into the SON reduced MAP increases and tail temperature decreases induced by RS. Also, NBQX enhanced RS-evoked tachycardia. SON treatment with DL-AP7 or NBQX reduced RS-induced increases in oxytocin, without affecting vasopressin plasma levels. Morever, NBQX enhanced RS-induced increases in plasma corticosterone level. DL-AP7 inhibited the RS-caused delayed anxiogenic-like effect.

NMDA and non-NMDA glutamate receptors in the SON facilitate pressor response and oxytocin release during RS. In addition, non-NMDA receptors exert an inhibitory influence RS-induced increases in heart rate and corticosterone release, whereas NMDA receptors contribute to the delayed expression of anxiety-like behaviors.

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.