The effect of repeated cocaine administration on serotonin2 (5-HT2) receptor function was examined in male rats. Rats were fitted with indwelling jugular catheters and subsequently received cocaine (15 mg/kg, i.p., b.i.d.) or saline for 7 days. Rats were challenged with the 5-HT2 agonist DOI (25, 100, 400 micrograms/kg, i.v.) or saline 42 hr and 8 days after cessation of chronic treatment. Serial blood samples were collected at various times after DOI challenge and analyzed for prolactin levels. DOI-induced head shakes and skin jerks were examined concurrently in the same subjects. After 42 hr of withdrawal, the stimulatory effects of DOI on prolactin release and shaking behavior were significantly enhanced in cocaine-treated rats. Conversely, the skin jerk response to DOI was not altered by prior cocaine exposure. After 8 days of withdrawal, the prolactin and head shake responses to DOI were still potentiated in cocaine-treated rats, but this effect was no longer statistically significant. The data indicate that chronic cocaine enhances the sensitivity of 5-HT2 receptor mechanisms. Our findings further suggest the possibility that altered 5-HT2 receptor function may be involved in the mood disturbances experienced by abstinent cocaine addicts.