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Proteomes 2018, 6(4), 41; https://doi.org/10.3390/proteomes6040041

Phosphoproteomic Analysis of the Amygdala Response to Adolescent Glucocorticoid Exposure Reveals G-Protein Coupled Receptor Kinase 2 as a Target for Reducing Motivation for Alcohol

1
Department of Psychiatry, University of Pittsburgh, 450 Technology Dr. Bridgeside Point II, Suite 223, Pittsburgh, PA 15219, USA
2
Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, CT 06536, USA
3
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06508, USA
4
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
5
Department of Psychiatry, Yale University, New Haven, CT 06508, USA
6
Department of Psychology, Yale University, New Haven, CT 06508, USA
*
Author to whom correspondence should be addressed.
Received: 28 August 2018 / Revised: 28 September 2018 / Accepted: 9 October 2018 / Published: 12 October 2018
(This article belongs to the Special Issue Neuroproteomics)
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Abstract

Early life stress is associated with risk for developing alcohol use disorders (AUDs) in adulthood. Though the neurobiological mechanisms underlying this vulnerability are not well understood, evidence suggests that aberrant glucocorticoid and noradrenergic system functioning play a role. The present study investigated the long-term consequences of chronic exposure to elevated glucocorticoids during adolescence on the risk of increased alcohol-motivated behavior, and on amygdalar function in adulthood. A discovery-based analysis of the amygdalar phosphoproteome using mass spectrometry was employed, to identify changes in function. Adolescent corticosterone (CORT) exposure increased alcohol, but not sucrose, self-administration, and enhanced stress-induced reinstatement with yohimbine in adulthood. Phosphoproteomic analysis indicated that the amygdala phosphoproteome was significantly altered by adolescent CORT exposure, generating a list of potential novel mechanisms involved in the risk of alcohol drinking. In particular, increased phosphorylation at serines 296–299 on the α2A adrenergic receptor (α2AAR), mediated by the G-protein coupled receptor kinase 2 (GRK2), was evident after adolescent CORT exposure. We found that intra-amygdala infusion of a peptidergic GRK2 inhibitor reduced alcohol seeking, as measured by progressive ratio and stress reinstatement tests, and induced by the α2AAR antagonist yohimbine. These results suggest that GRK2 represents a novel target for treating stress-induced motivation for alcohol which may counteract alterations in brain function induced by adolescent stress exposure. View Full-Text
Keywords: adolescence; corticosterone; proteomics; yohimbine; progressive ratio; reinstatement; ethanol adolescence; corticosterone; proteomics; yohimbine; progressive ratio; reinstatement; ethanol
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Bertholomey, M.L.; Stone, K.; Lam, T.T.; Bang, S.; Wu, W.; Nairn, A.C.; Taylor, J.R.; Torregrossa, M.M. Phosphoproteomic Analysis of the Amygdala Response to Adolescent Glucocorticoid Exposure Reveals G-Protein Coupled Receptor Kinase 2 as a Target for Reducing Motivation for Alcohol. Proteomes 2018, 6, 41.

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