Many of the withdrawal symptoms reported by human cocaine users are thought to be correlated with serotonergic dysfunction. To explore the neurochemical basis for this hypothesis, we used in vivo microdialysis to monitor extracellular serotonin (5-HT) in the nucleus accumbens of the rat both during and for several hours after unlimited-access intravenous cocaine self-administration. Self-administration of cocaine produced an increase of approx. 340% of baseline in the dialysate concentration of 5-HT that persisted for the entire 12 h session. During the first 6 h after self-administration, dialysate 5-HT levels were significantly decreased to 41% of pre-session levels and 25% of the levels in drug-naive control animals. The effects of cocaine exposure on basal extracellular 5-HT concentrations were also examined using a quantitative microdialysis method (Difference Method). Rats withdrawing from extended-access cocaine self-administration displayed significantly lower extracellular 5-HT levels (0.6 +/- 0.3 nM) than either drug-naive control animals (2.0 +/- 0.5 nM) or animals which received daily 3-h self-administration training sessions only (limited-access; 1.4 +/- 0.2 nM). Together these results indicate that extracellular 5-HT is significantly decreased in the nucleus accumbens during withdrawal from cocaine self-administration. The severity of this decrease is contingent on the length of time cocaine is self-administered.