It was previously reported that chronic food restriction and maintenance of rats at 75-80% of initial
body weight enhanced the reward-potentiating effect of
D-amphetamine in the lateral hypothalamic self-stimulation (LHSS) paradigm. Moreover, the enhancement reversed in parallel with
body weight recovery when ad libitum access to food was reinstated. The present study tested the hypothesis that hypoleptinemia during food restriction is necessary for expression of enhanced
drug reward. In Experiment 1, intracerebroventricular (i.c.v.) infusion of
leptin (0.5 microg/0.5 microl/hr for 8 days) in food-restricted rats did not alter the rewarding effect of
D-amphetamine (0.5 mg/kg, i.p.). Considering that i.c.v.
leptin may not diffuse into deep brain regions where direct effects on
drug reward sensitivity may be exerted, effects of acute bilateral microinjection of
leptin (0.5 microg) in ventral tegmental area and nucleus accumbens were tested in Experiment 2 and found to have no effect. In Experiment 3, chronic i.c.v.
leptin infusion in ad libitum fed rats decreased food intake and
body weight and enhanced the rewarding effect of
D-amphetamine. Sensitivity to
D-amphetamine returned to normal as
body weight recovered following cessation of
leptin infusion. This result suggests that
weight loss, whether from
hormone-induced appetite suppression or experimenter-imposed food restriction, is sufficient to enhance
drug reward sensitivity. Experiment 4 tested whether food restriction in the absence of
body weight loss alters
drug reward sensitivity. Rats received chronic i.c.v. infusion of the orexigenic
melanocortin receptor antagonist,
SHU9119 (0.02 microg/0.5 microl/hr for 12 days), and a subset were pair-fed to vehicle-infused controls. Although these subjects ingested approximately 50% of the amount of food ingested by free-feeding SHU9119-infused rats, they displayed no
weight loss and no change in sensitivity to
D-amphetamine. Together, results of this study support the importance of
weight loss, but not
leptin, in the enhancement of
drug reward sensitivity.