Intracellular recordings were made in vitro from pyramidal neurons in layer V of the anterior cingulate cortex of the rat. 5-Hydroxytryptamine (5-HT) reduced the amplitude of the excitatory postsynaptic potential; receptor-selective agonists and antagonists indicated that this resulted from activation of the 5-HT1B receptor. The action of 5-HT was enhanced by cocaine (300 nM-3 microM); 1 microM cocaine increased sensitivity to 5-HT about 10-fold. The results suggest that cocaine is similarly effective to potentiate the action of 5-HT in the prefrontal cortex as in other brain regions. This may contribute to its overall in vivo effects.