CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in c57bl/6j mice independent of the HPA axis

Abstract

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, α-helical CRF 9-41 (0, 1, 5, 10 g/1 l). The contribution of central CRF type 2 receptor (CRF 2 R) signaling was assessed with i.c.v. infusion of the selective CRF 2 R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 g/1 l). The role of the hypothalamic-pituitary-adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 mg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 mg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF 1 R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 g dose of α-helical CRF 9-41 significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF 1 R and CRF 2 R signaling, such that blockade of CRF 1 R or activation of CRF 2 R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior. © 2010 Nature Publishing Group All rights reserved.