Food deprivation (FD) or restriction augments the locomotor activating and reinforcing effects of drugs of abuse. It has been proposed that these effects might be mediated by FD-induced increase in plasma levels of ghrelin, a 28-amino acid orexigenic peptide demonstrated to functionally interact with the mesolimbic dopaminergic system. However, a role for ghrelin has been demonstrated only with psychostimulant drugs and alcohol associated behaviors. We therefore examined the role of ghrelin in ongoing heroin self-administration and FD-induced reinstatement of extinguished heroin seeking. As expected, infusions of ghrelin [0.0, 1.5 and 3.0 µg/rat, intracerebroventricular (i.c.v.)] produced increases in breakpoints on a progressive ratio schedule of heroin reinforcement. In contrast, central administration of a ghrelin receptor antagonist, [D-Lys-3]-GHRP-6 (0.0, or 20.0 µg/rat, i.c.v.) had no effect on ongoing heroin self-administration under a fixed-ratio 1 schedule, or on FD-induced reinstatement of heroin seeking. These results suggest that signals mediated through ghrelin receptors play a limited role in FD-induced augmentation of heroin reinforcement and reinstatement of extinguished heroin seeking.

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.