BIPHASIC EFFECTS OF SIGMA-LIGANDS ON THE NEURONAL RESPONSE TO N-METHYL-D-ASPARTATE

Previous studies from our laboratory have demonstrated that low doses of selective sigma (sigma) ligands potentiate the neuronal response to N-methyl-D-aspartate (NMDA) in the CA(3) region of the rat dorsal hippocampus. Sertraline and clorgyline, two antidepressant drugs with a high affinity for receptors, also potentiate, at low doses, the NMDA response; however, when administered at higher sigma doses, the degree of potentiation induced by these two ligands progressively decreases (Bergeron et al. 1993). In the present experiments, the selective sigma ligands DTG, (+)pentazocine, BD-737, JO-1784 and L-687,384 were studied to determine if they would also generate bell-shaped dose-response curves. These ligands were administered intravenously at doses ranging from 1 mu g/kg to 1 mg/kg or applied by microiontophoresis. They potentiated selectively, with bell-shaped dose-response curves, the NMDA-induced activation of pyramidal neurons in the CA(3) region of the rat dorsal hippocampus. The potentiation of the NMDA response following the intravenous administration of a low dose of a sigma ligand persisted for at least 60 min, after which point in time a second injection of the same dose induced the same degree of potentiation. Moreover, a sustained potentiation was obtained during prolonged microiontophoretic applications of a sigma ligand. These two latter series of observations suggest that the lack of effect of the high doses of a ligands is not related to a rapid desensitisation of sigma receptors. This biphasic effect of ligands might be due to the concomitant actions of these sigma ligands on distinct subtypes of sigma receptors.