Studies in rats have shown that intermittent footshock stress reinstates drug seeking after prolonged drug-free periods. Recently, we found that another environmental stressor, acute 1 d food deprivation, potently reinstates heroin seeking in rats. Here we report that this effect of food deprivation can be blocked by leptin, a hormone involved in the regulation of energy balance and food intake. Rats were trained to self-administer heroin (0.05-0.1 mg/kg, i.v., per infusion, three 3 hr sessions per day) for 8-10 d. The heroin-reinforced behavior was then extinguished for 10-13 d, during which lever presses had no reinforced consequences. Subsequently, rats were tested for reinstatement after 1 d of food deprivation (experiment 1) or exposure to intermittent footshock (15 min, 0.6 mA) and heroin priming injections (0.25 mg/kg, s.c.) (experiment 2). Acute food deprivation reinstated heroin seeking, an effect that was attenuated by leptin (2 or 4 microgram/rat, i.c.v.; two infusions, given 21 hr and 20-30 min before the start of the test sessions). In contrast, leptin had no effect on reinstatement of heroin seeking induced by intermittent footshock or priming injections of heroin. These data indicate that food deprivation can provoke relapse to heroin seeking via a leptin-dependent mechanism, which is not involved in relapse induced by footshock stress or reexposure to heroin.