Effects of central leptin infusion on the reward-potentiating effect of D-amphetamine

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.