Since reserpine precipitates depression in some hypertensive patients, we tested this drug on our animal model of depression. The present experiment was designed to measure the effects of chronic reserpine treatment on 5-hydroxytryptophan (5-HTP) induced behavioral depression in rats trained on a food reinforcement operant schedule. Based on the Aprison et al. model of depression involving the serotonergic system, we predicted the development of receptor supersensitivity of postsynaptic serotonin (5-HT) receptors due to the decreased release of this neurotransmitter as a consequence of chronic reserpine treatment. Rats were trained on a VI 1 reinforcement schedule and then divided into 3 chronic treatment groups. One received daily injections of a placebo, another 0.025 mg/kg reserpine and the third 0.05 mg/kg reserpine. We found that 5-HTP induced behavioral depression was potentiated in rats chronically treated with reserpine, thus suggesting the development of supersensitive 5-HT receptors. These results support the hypothesis that in some types of human depression a decreased release of 5-HT occurs of sufficient duration to permit the subsequent development of supersensitive 5-HT receptors.