We have shown previously that low doses of selective sigma (sigma)- receptor ligands potentiate the excitatory response of pyramidal neurons to NMDA in the CA3 region of the dorsal hippocampus in the rat. Because progesterone competitively displaces the binding of the ligand N-[3H]allyl-normetazocine (SKF-10,047), the present studies were undertaken to determine in vivo the effect of neuroactive steroids on NMDA-induced excitation of rat CA3 pyramidal neurons. Low doses of dehydroepiandrosterone (DHEA) potentiated the NMDA response selectively and dose-dependently. The effect of DHEA was reversed by the selective sigma antagonist N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl)- ethylamine monohydrochloride (NE-100) and by haloperidol, but not by spiperone. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by nonsteroidal sigma ligands. Neither pregnenolone nor pregnenolone sulfate had any effect on the NMDA response--nor did they antagonize the potentiation of the NMDA response induced by DHEA and by nonsteroidal sigma ligands. A pertussis toxin pretreatment, which inactivates Gi/o-proteins, abolished the potentiating effects of DHEA. Ovariectomy enhanced the potentiation of the NMDA response by the nonsteroidal sigma ligand di(2-tolyl)guanidine (DTG). There was a reciprocal occlusion of the effects of DHEA and DTG; DTG did not potentiate the NMDA response further after DHEA, and DHEA did not do so after DTG. These results suggest that some neuroactive steroids modulate the NMDA response via sigma receptors.