Social defeat stress enhances the rewarding effects of cocaine through α1A adrenoceptors in the medial prefrontal cortex of mice

Atsushi Saito; Haruka Murata; Kazuhei Niitani; Junpei Nagasaki; Atsuki Otoda; Yusuke Chujo; Junko Yanagida; Naoya Nishitani; Satoshi Deyama; Katsuyuki Kaneda

doi:10.1016/j.neuropharm.2023.109757

Social defeat stress enhances the rewarding effects of cocaine through α_1A adrenoceptors in the medial prefrontal cortex of mice

Neuropharmacology. 2024 Jan 1:242:109757. doi: 10.1016/j.neuropharm.2023.109757. Epub 2023 Oct 13.

Affiliations

¹ Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
² Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan. Electronic address: k-kaneda@p.kanazawa-u.ac.jp.

PMID: 37839511
DOI: 10.1016/j.neuropharm.2023.109757

Abstract

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 α₁ adrenoceptors, but not β adrenoceptors, suppressed this increase. Fiber photometry recordings with GRAB_NE1m 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 α₁ adrenoceptor antagonist. In vitro whole-cell recordings demonstrated that silodosin, an α_1A, but not α_1B or α_1D, 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_1A 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_1A 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.

Keywords: Cocaine; Conditioned place preference; Noradrenaline; Social defeat stress; α(1A) adrenoceptor.

MeSH terms

Animals
Cocaine* / pharmacology
Male
Mice
Prefrontal Cortex
Receptors, Adrenergic
Reward
Social Defeat
Stress, Psychological / psychology

Substances

Cocaine
Receptors, Adrenergic
BCL2-related protein A1