Neuropeptide-Y (NPY) is the most abundant and widely distributed
peptide in the mammalian central nervous system and increases feeding behavior through actions at the Y5 receptor subtype. Recent pharmacological evidence indicates that NPY activity at this receptor subtype can modulate
ethanol reinforcement. The purpose of this study was to determine if
NPY Y5 receptor antagonism reduces
ethanol self-administration and reinforcement in a rodent genetic animal model of
alcoholism. Selectively inbred alcohol-preferring (iP) rats were trained to voluntarily consume
ethanol (10% vol/vol) versus H2O in a 24-h two-bottle choice test. An additional group of iP rats was trained in operant
ethanol self-administration to lever press on a fixed-ratio 1 schedule for
ethanol (10% vol/vol) reinforcement. Following establishment of baseline intake or
ethanol-reinforced responding, iP rats were injected with L-152,804 (0-20 mg/kg) prior to two-bottle or operant
ethanol self-administration sessions. In the two-bottle choice test, L-152,804 (3 and 10 mg/kg, ip) significantly reduced
ethanol intake (g/kg) at 4- and 6-h postinjection and had no effect on food intake. In the operant procedure, L-152,804 (10 and 20 mg/kg, ip) significantly reduced both the dosage of self-administered
ethanol (g/kg/1-h) and the total number of
ethanol-reinforced responses. No effect was observed on latency to the first response or the number of inactive lever presses. These results indicate that blockade of
NPY Y5 receptor activity decreases both voluntary
ethanol drinking and
ethanol reinforcement in a rodent genetic animal model of
alcoholism. For this reason,
NPY Y5 receptor antagonists may be useful in medical management of
alcohol abuse and
alcoholism in the human population.