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.
Highlights
Chronic stress is an environmental factor known to increase the risk for psychiatric disorders, including alcohol use disorders
In Experiment 1 of the current study, we demonstrate that under certain training conditions, male rats exposed to CORT in adolescence demonstrate an increased motivation for alcohol, as evidenced by increased operant alcohol self-administration and yohimbine-induced reinstatement of alcohol-seeking behavior in adulthood, whereas responding for sucrose was unchanged
In the present series of studies, we first examined the impact of chronic exposure to the glucocorticoid stress hormone corticosterone (CORT) during adolescence (PND 30–50) on ethanol-motivated behaviors and on the amygdala phosphoproteome (Experiment 1)
Summary
Chronic stress is an environmental factor known to increase the risk for psychiatric disorders, including alcohol use disorders. Chronic stress during critical developmental periods can have long-lasting effects on alcoholism risk [1,2,3,4,5]. We have found that chronic exposure to the glucocorticoid stress hormone corticosterone (CORT). During adolescence, using an established procedure that produces a depression-like syndrome in adults [8,9], increases impulsivity on the delay-discounting test of impulsive choice, indicating that adolescent CORT has long-term effects on behavior [10]. Impulsivity on delay discounting tasks is frequently associated with presence of alcohol use disorders, and it is a possible risk factor for alcoholism [11]
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