The mood-altering properties of amphetamine (AMPH) in humans (euphoria and depression) have been postulated to be related to the increases and decreases respectively which this drug produces in the sensitivity of the reward system of the brain. The present study further evaluated this relationship by testing the effects of chronic reserpine (RES), another treatment that produces depression in humans, on self-stimulation responding. Separate groups of animals implanted with stimulating electrodes in the medial forebrain bundle were administered daily injections of saline, d-AMPH (5 mg/kg X 7 days followed by 10 mg/kg X 7 days), or RES (0.05 mg/kg X 18 days). At treatment termination, both drug groups showed a significant elevation of the reinforcement threshold, with no recovery occurring during 18 subsequent days. Thus, drug-induced depression of self-stimulation responding may serve as an animal model for studying the underlying physiological basis for clinical depression, or at the very least, for drug-induced depression.