Differential importance of nucleus accumbens Ox1Rs and AMPARs for female and male mouse binge alcohol drinking

Claudina Kwok,Laura Li,Margaret Walsh,Jihwan Yu,Kelly Lei,Lexy Anderson,Shahbaj Ghotra,Frederic Woodward Hopf,Vincent Pedrozo

doi:10.1038/s41598-020-79935-2

Abstract

Alcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking. Thus, it is critically important to understand signaling differences underlying alcohol consumption across the sexes. Orexin-1 receptors (Ox1Rs) can strongly promote motivated behavior, and we previously identified Ox1Rs within nucleus accumbens shell (shell) as crucial for driving binge intake in higher-drinking male mice. Here, shell Ox1R inhibition did not alter female mouse alcohol drinking, unlike in males. Also, lower dose systemic Ox1R inhibition reduced compulsion-like alcohol intake in both sexes, indicating that female Ox1Rs can drive some aspects of pathological consumption, and higher doses of systemic Ox1R inhibition (which might have more off-target effects) reduced binge drinking in both sexes. In contrast to shell Ox1Rs, inhibiting shell calcium-permeable AMPA receptors (CP-AMPARs) strongly reduced alcohol drinking in both sexes, which was specific to alcohol since this did not reduce saccharin intake in either sex. Our results together suggest that the shell critically regulates binge drinking in both sexes, with shell CP-AMPARs supporting intake in both sexes, while shell Ox1Rs drove drinking only in males. Our findings provide important new information about sex-specific and -general mechanisms that promote binge alcohol intake and possible targeted therapeutic interventions.

Highlights

Alcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking
In seeking the critical mechanisms that drive binge drinking, we have focused on the nucleus accumbens (NAcb) shell and the contribution of orexin-1-receptors (Ox1Rs) and AMPA-type glutamate receptors (AMPARs)
Aversion-resistant alcohol drinking was reduced by lower doses of systemic Orexin-1 receptors (Ox1Rs) inhibition in males and females, showing that Ox1Rs can regulate at least some forms of alcohol intake in females

Summary

Introduction

Alcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking. Lower dose systemic Ox1R inhibition reduced compulsion-like alcohol intake in both sexes, indicating that female Ox1Rs can drive some aspects of pathological consumption, and higher doses of systemic Ox1R inhibition (which might have more off-target effects) reduced binge drinking in both sexes. The shell is a critical regulator of numerous motivated and addiction-related behaviors[22,23,24,25] and compulsion-like b ehaviors[26,27,28], including where shell inhibition reduces alcohol drinking but not sweet fluid intake or locomotor a ctivity[29,30,31,32,33,34,35,36]. Shell CP-AMPARs are known to promote several addiction-related behaviors (reviewed in22), making it imperative to know whether CP-AMPARs in shell are important modulators of alcohol binge consumption

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Conclusion