The present study was designed to examine the effects of chronic cocaine administration on the extracellular response of serotonin (5-HT) and dopamine (DA) to a peripheral cocaine injection using in vivo brain microdialysis in awake rats. Two different dual probe preparations were used: One group of animals had guide cannulae aimed at the ventral tegmental area (VTA) and nucleus accumbens (N ACC) and a second group of animals had guide cannulae aimed at the dorsal raphe nucleus (DRN) and N ACC. Rats from both groups were given daily injections of either cocaine (20 mg/kg i.p.) or saline (0.9%; 0.05 ml/kg i.p.) for 10 consecutive days. On day 11, baseline dialysate levels of DA, 5-HT, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were obtained from either the N ACC and VTA or the N ACC and DRN, followed by a 10 mg/kg i.p. cocaine injection and an additional 150 min of dialysate sampling. The percent baseline increases of both 5-HT and DA were significantly higher in the N ACC, VTA, and DRN of animals that received daily injections of cocaine compared with saline controls (p < 0.05, in each region). Maximum dialysate 5-HT concentrations after cocaine challenge were significantly higher in the N ACC and VTA (p < 0.05) and DRN (p < 0.01) of chronically treated animals compared with saline controls. Maximum dialysate DA concentrations were significantly higher in the N ACC and DRN (p < 0.05) of chronically treated animals compared with saline controls. There was no significant difference between acute and chronic animals in the maximum dialysate DA concentration from the VTA after cocaine challenge.(ABSTRACT TRUNCATED AT 250 WORDS)