In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+)-pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D-aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region.