A role for neuropeptide Y Y5 but not the Y1-receptor subtype in food deprivation-induced reinstatement of heroin seeking in the rat

Rational and objectives Neuropeptide Y (NPY), an orexigenic peptide that is released during periods of food restriction, has been shown to have a significant modulatory impact on drug-related behaviors. We have previously reported that both acute food deprivation (FD) and NPY injections can reinstate extinguished drug-seeking behavior, a proposed animal model of relapse to drug abuse. However, it is not clear whether the FD effect on drug seeking is dependent on NPY transmission. Here, we used the reinstatement model to assess the role of NPY Y1 and Y5-receptor-mediated transmission in FD-induced reinstatement of heroin seeking. Methods Rats were trained to self-administer heroin for 10-12 days (0.1 mg/kg/infusion/intravenous). Animals then underwent extinction training followed by drug-seeking reinstatement tests under 21 h of FD and sated conditions. Results Injections of a novel NPY Y5-receptor antagonist, Lu AA33810 (0.0, 1.0, or 30.0 mg/kg/IP), resulted in a significant attenuation of FD-induced reinstatement of extinguished heroin seeking. However, no significant effects on reinstatement were found for the Y1-receptor antagonist, BIBO 3304 (0.0, 5.0, or 10.0 nmol/intracerebroventricular). Conclusions These results suggest that while signals mediated through NPY Y1 receptors play a modest role in reinstatement, activation of Y5 receptors has a critical function in FD-induced reinstatement of heroin-seeking behavior.