Abstract

It has been often noted that natural and drug rewards show similar behavioral characteristics, and share some of the underlying neural pathways. The orexigenic peptides, neuropeptide-Y (NPY) and ghrelin, traditionally involved in homeostatic regulation of feeding, have been shown to have a significant modulatory impact on drug-related behaviors. In the experiments described in the present thesis, we first used an animal model of relapse to drug abuse, the reinstatement model, to assess the role of NPY Y1 and Y5-receptor-mediated transmission in food deprivation (FD)-induced reinstatement of heroin seeking. Results demonstrated that injections of a novel NPY Y5receptor antagonist, Lu AA33810 (0.0, or 30.01kg/IP), resulted in a significant attenuation of FD-induced reinstatement of extinguished heroin seeking. However no effects were found for the Y1-receptor antagonist, BIBO-3304 (0.0,5.0, or 10.0 nmol/ICV) or the Y5-receptor antagonist, L-152-804 (0.0, or 20.0 og/ICV). We then studied the role of ghrelin in on-going heroin self-administration and FD-induced reinstatement of extinguished . heroin seeking. Surprisingly, although infusions of ghrelin (0.0, 1.5, and 3.0 og/rat, i.c.v.) produced increases in breakpoints on a progressive ratio schedule of reinforcement, antagonism of ghrelin receptors had no effect on on-going heroin self-administration, or on FD-induced reinstatement of heroin seeking. These results suggest that while signals mediated through NPY Y1 and ghrelin receptors play a modest role in drug reinforcement and reinstatement, activation of Y5-receptors has a critical function in FD-induced reinstatement of heroin seeking behavior.