Neuropeptide Y Y5 receptor antagonism attenuates addictive effects of cocaine

Abstract

Neuropeptide Y (NPY) has been implicated in addiction to drugs of abuse, including cocaine. For instance, chronic cocaine treatment is associated with decreased NPY levels in the nucleus accumbens, a key region in addiction, and intra-accumbal injection of NPY causes place-preference. At present, the NPY receptors mediating addiction-related effects of NPY have not been determined. The present study explored the potential role of the NPY Y5 receptor, testing the Y5 antagonist L-152,804 (3, 10, and 30 mg/kg; p.o.) and Y5 knockout mice in two mice models of cocaine addiction: acute self-administration (ASA) and conditioned place-preference (CPP). In ASA, drug-naïve mice were allowed to self-administer cocaine (0.01-1 mg/kg/infusion) or saline i.v. for 30 minutes, following oral pre-treatment with L-152,804 or vehicle. L-152,804 significantly decreased nose-poking for the peak dose of cocaine (0.03 mg/kg/infusion) at the two highest doses and shifted the dose-response curve for cocaine to the right and downward. Consistent with the Y5 antagonist results, Y5 knockout mice did not self-administer cocaine in the tested dose-range while wildtype mice did. In CPP, mice were conditioned with i.p. injections of cocaine (10 mg/kg) or saline following oral pretreatment with L-152,804 or vehicle. L-152,804 did not reduce cocaine-induced CPP, but caused significantly faster extinction at all doses and a significant reduction in relapse at 30 mg/kg. Likewise, Y5 knockout mice did develop CPP for cocaine like wildtype mice, but faster extinction was observed and relapse was absent in the mutant mice. These data indicate that Y5 antagonism may attenuate addictive properties of cocaine and suggest that Y5 receptors could be a target for future treatment of cocaine addiction.