Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis in Socially Defeated and Non-stressed Mice with a History of Chronic Alcohol Intake.

Lucas Albrechet-Souza,Rosa M M De Almeida,Rodrigo Grassi-Oliveira,Thiago W Viola,Klaus A Miczek

doi:10.3389/fphar.2017.00762

Abstract

Stress exposure has been identified as one risk factor for alcohol abuse that may facilitate the transition from social or regulated use to the development of alcohol dependence. Preclinical studies have shown that dysregulation of the corticotropin releasing factor (CRF) neurotransmission has been implicated in stress-related psychopathologies such as depression and anxiety, and may affect alcohol consumption. The bed nucleus of the stria terminalis (BNST) contains CRF-producing neurons which seem to be sensitive to stress. In this study, adult male C57BL/6 mice previously defeated in resident-intruder confrontations were evaluated in the elevated plus-maze and tail suspension test. Mice were also tested for sweet solution intake before and after social stress. After having had continuous access to ethanol (20% weight/volume) for 4 weeks, control and stressed mice had CRF type 1 (CRFR1) or type 2 (CRFR2) receptor antagonists infused into the BNST and then had access to ethanol for 24 h. In separate cohorts of control and stressed mice, we assessed mRNA levels of BNST CRF, CRFR1 and CRFR2. Stressed mice increased their intake of sweet solution after ten sessions of social defeat and showed reduced activity in the open arms of the elevated plus-maze. When tested for ethanol consumption, stressed mice persistently drank significantly more than controls during the 4 weeks of access. Also, social stress induced higher BNST CRF mRNA levels. The selective blockade of BNST CRFR1 with CP376,395 effectively reduced alcohol drinking in non-stressed mice, whereas the selective CRFR2 antagonist astressin2B produced a dose-dependent increase in ethanol consumption in both non-stressed controls and stressed mice. The 10-day episodic defeat stress used here elicited anxiety- but not depressive-like behaviors, and promoted an increase in ethanol drinking. CRF-CRFR1 signaling in the BNST seems to underlie ethanol intake in non-stressed mice, whereas CRFR2 modulates alcohol consumption in both socially defeated and non-stressed mice with a history of chronic intake.

Highlights

Alcoholics often refer to stress and anxiety as strong motivators for drinking (Ludwig and Wikler, 1974; Litman et al, 1983; Sinha, 2009)
Exposures to corticosterone and the pharmacological stressor yohimbine upregulate corticotropin releasing factor (CRF) mRNA expression in the bed nucleus of the stria terminalis (BNST) (Makino et al, 1994; Funk D. et al, 2006). Both CRF receptors are expressed within the BNST (Van Pett et al, 2000; Dabrowska et al, 2011; Rinker et al, 2017), few experimental studies have directly examined the role of BNST CRF in the interaction between stress and alcohol consumption, and little is known about the specific contribution of CRFR2
The current experiments were designed to test the hypothesis that brief episodes of social defeat stress can elicit dysregulated behaviors in adult C57BL/6 mice, including anxiety- or depressive-like symptoms and excessive ethanol consumption, as well as neuroadaptations of the CRF system in the BNST

Summary

INTRODUCTION

Alcoholics often refer to stress and anxiety as strong motivators for drinking (Ludwig and Wikler, 1974; Litman et al, 1983; Sinha, 2009). Exposures to corticosterone and the pharmacological stressor yohimbine upregulate CRF mRNA expression in the BNST (Makino et al, 1994; Funk D. et al, 2006) Both CRF receptors are expressed within the BNST (Van Pett et al, 2000; Dabrowska et al, 2011; Rinker et al, 2017), few experimental studies have directly examined the role of BNST CRF in the interaction between stress and alcohol consumption, and little is known about the specific contribution of CRFR2. The current experiments were designed to test the hypothesis that brief episodes of social defeat stress can elicit dysregulated behaviors in adult C57BL/6 mice, including anxiety- or depressive-like symptoms and excessive ethanol consumption, as well as neuroadaptations of the CRF system in the BNST. We investigated the effects of BNST treatment with either selective CRFR1 or CRFR2 antagonists on free-choice home cage ethanol drinking in non-stressed controls and stressed mice with a history of continuous access to ethanol

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION