We used standard intracellular current-clamp electrophysiological recording techniques in a brain slice preparation to determine whether chronic cocaine administration would: 1) alter the sensitivity of septal neurons to exogenous serotonin (5-HT) application and 2) modify the interaction of 5-HT with cocaine in vitro. Recordings were made from neurons in rat brain slices that contained the dorsolateral septal nucleus obtained from drug naive (DN) rats or rats give cocaine (15mg/kg, i.p., 2 X daily) for periods of 7 (CC7) or 14 (CC14) days. In addition, some of these rats also received intraventricular pertussis toxin (PTX) injections 2 to 3 days before experimentation to abolish the postsynaptic 5-HT1A receptor-mediated membrane hyperpolarization and to unmask a 5-HT-induced depolarization. In comparison with DN and CC7, CC14 slices showed an increased sensitivity to 5-HT as revealed by a 2-fold leftward shift in the 5-HT EC50 values. In addition, in PTX-CC14 slices, 5-HT could hyperpolarize the cell membrane, whereas the 5-HT1A agonist, 8-OH-DPAT, and the gamma-aminobutyric acidB agonist, baclofen, failed to do so. We also observed that cocaine (3 microM) in CC14 slices did not significantly potentiate and prolong 5-HT hyperpolarizations as found in DN slices. We conclude that in the CC14 septal slice a 5-HT transporter is down-regulated and that an atypical 5-ht response can be elicited. Additionally, 5-HT1A receptor up-regulation and/or 5-HT2 receptor down-regulation may contribute to the increased sensitivity of septal neurons to 5-HT.