Peripheral and Central Administration of a Selective Neuropeptide Y Y1 Receptor Antagonist Suppresses Ethanol Intake by C57BL/6J Mice


  • This work was supported by NIH Grants AA13573 and AA011605 and by Merck & Co., Inc.

Reprint requests: Todd E. Thiele, PhD, Department of Psychology, University of North Carolina, Davie Hall, CB 3270, Chapel Hill, NC 27599-3270; Fax: 919-962-2537; E-mail:


Background: Neuropeptide Y (NPY) is a 36–amino acid neuromodulator that is expressed throughout the central nervous system. Recent genetic and pharmacological evidence suggests that the NPY Y1 receptor modulates ethanol intake. To further characterize the role of the Y1 receptor, we examined voluntary ethanol consumption by mice after administration of [(−)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-tiazol-2-yl)ethyl]-4-morpholinopyridine] (compound A), a novel and selective Y1 receptor antagonist (Y1RA) that acts centrally on brain receptors when administered peripherally.

Methods: C57BL/6J mice were habituated to drinking a 10% (v/v) ethanol solution by using a two-bottle-choice procedure and were then given an intraperitoneal (ip) injection (5 ml/kg) of the Y1RA (0, 25, 50, or 75 mg/kg). In a second study, mice were given intracerebroventricular infusion of the Y1RA (0, 30, or 100 μg). Finally, we determined whether the Y1RA alters open-field locomotor activity, ethanol-induced sedation (3.8 g/kg, ip), or blood ethanol levels.

Results: Relative to control treatment, ip injection (50 and 75 mg/kg) and intracerebroventricular infusion (100 μg) of the Y1RA significantly reduced ethanol consumption and food intake without altering water drinking. However, the Y1RA did not alter open-field locomotor activity, ethanol-induced sedation, or blood ethanol levels.

Conclusions: These data indicate that acute blockade of the NPY Y1 receptor with a systemically bioavailable NPY Y1RA reduces voluntary ethanol consumption by C57BL/6J mice. These results are consistent with observations that hypothalamic infusion of NPY increases ethanol drinking by rats.