NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking

Kristen E Pleil,Jennifer A Rinker,Emily G Lowery-Gionta,Christopher M Mazzone,Nora M Mccall,Alexis M Kendra,David P Olson,Bradford B Lowell,Kathleen A Grant,Todd E Thiele,Thomas L Kash

doi:10.1016/j.npep.2015.11.009

Abstract

Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

Highlights

Binge alcohol drinking is the most common form of excessive alcohol consumption and contributes to a host of long-term negative health consequences, including alcohol dependence and anxiety disorders[5,6,7,8,9]
We found that neuropeptide Y (NPY) Y1 receptor (Y1R) activation in the bed nucleus of the stria terminalis (BNST) suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission in corticotropin-releasing factor (CRF) neurons via a novel, Gi-mediated, protein kinase A (PKA)-dependent postsynaptic mechanism
We found that infusion of a Y1R agonist into the BNST, but not adjacent dorsal striatum, reduced binge alcohol consumption (Fig. 1b,c, Supplementary Fig. 1b, Supplementary Fig. 2a), while infusion of a Y1R antagonist into the BNST increased alcohol consumption (Supplementary Fig. 1c,d), consistent with our hypothesis that Y1R in the BNST is a neural substrate for NPY’s anti-drinking effects

Summary

Introduction

Binge alcohol drinking is the most common form of excessive alcohol consumption and contributes to a host of long-term negative health consequences, including alcohol dependence and anxiety disorders[5,6,7,8,9]. Repeated bouts of binge-induced alcohol intoxication followed by withdrawal are hypothesized to cause aberrant plasticity in brain regions that underlie reward-seeking behavior and stress responsivity, leading to an increased negative affective state that drives increased alcohol consumption[5, 9,10,11]. These effects may be mediated by altered signaling of endogenous stress and anti-stress neuropeptide systems that functionally oppose each other, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY)[10, 12,13,14]. Pharmacological manipulations in the BNST can alter alcohol drinking behaviors[24, 25] and chronic alcohol exposure and withdrawal alter the function and plasticity of BNST neurons[26, 27], the role of NPY signaling in the BNST to regulate alcohol drinking has not been evaluated

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Results

Discussion

Conclusion