In the CA3 region of rat dorsal hippocampus, several σ ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-l-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 a receptors. The present experiments were carried out to determine the effects of these σ ligands and of neuropeptide Y, in the CAI 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 CAI 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 a receptors. Since ( + )-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the a, subtype of receptors, these data suggest the existence of two subtypes ofσ 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.