[Show abstract][Hide abstract] ABSTRACT: Frequent binge drinking has been linked to heart disease, high blood pressure, type 2 diabetes, and the development of ethanol dependence. Thus, identifying pharmaceutical targets to treat binge drinking is of paramount importance. Here we employed a mouse model of binge-like ethanol drinking to study the role of neuropeptide Y (NPY). To this end, the present set of studies utilized pharmacological manipulation of NPY signaling, immunoreactivity (IR) mapping of NPY and NPY receptors, and electrophysiological recordings from slice preparations of the amygdala. The results indicated that central infusion of NPY, a NPY Y1 receptor (Y1R) agonist, and a Y2R antagonist significantly blunted binge-like ethanol drinking in C57BL/6J mice (that achieved blood ethanol levels >80 mg/dl in control conditions). Binge-like ethanol drinking reduced NPY and Y1R IR in the central nucleus of the amygdala (CeA), and 24 h of ethanol abstinence after a history of binge-like drinking promoted increases of Y1R and Y2R IR. Electrophysiological recordings of slice preparations from the CeA showed that binge-like ethanol drinking augmented the ability of NPY to inhibit GABAergic transmission. Thus, binge-like ethanol drinking in C57BL/6J mice promoted alterations of NPY signaling in the CeA, and administration of exogenous NPY compounds protected against binge-like drinking. The current data suggest that Y1R agonists and Y2R antagonists may be useful for curbing and/or preventing binge drinking, protecting vulnerable individuals from progressing to the point of ethanol dependence.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2012; 37(6):1409-21. DOI:10.1038/npp.2011.327 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Numerous rodent and human studies have demonstrated that neuropeptide Y (NPY) is involved in the regulation of anxiety-related behaviors. In this study, we examined whether there were differences in NPY signaling between two inbred mouse strains (C57BL/6J and DBA/2J) that exhibit divergent basal and stress-induced anxiety phenotypes. We focused on the bed nucleus of the stria terminals (BNST), a structure in the extended amygdala that is important for the regulation of anxiety-like behavior and contains NPY receptors. While results from whole-cell voltage-clamp recordings and immunofluorescence histochemistry revealed no significant basal differences in NPY signaling or NPY and NPY Y2 receptor (Y2R) expression in the BNST, these measures were differentially altered by chronic restraint stress. Ten days of chronic restraint stress increased basal GABAergic transmission and decreased NPY's ability to inhibit evoked GABAergic transmission in the dorsolateral BNST (dlBNST) via Y2R in DBA/2J, but not C57BL/6J, mice. Additionally, restraint stress increased NPY and Y2R expression across subregions of the BNST of DBA/2J mice 24 h after the last stress exposure, but no changes were observed in C57BL/6J mice. Together, these results suggest that chronic restraint stress engages the NPY system and alters NPY modulation of inhibitory transmission in the dlBNST of DBA/2J mice, but not C57BL/6J mice, which may be related to increased expression of anxiety-related behaviors in this strain.