MODULATION OF THE NEURONAL RESPONSE TO N-METHYL-D-ASPARTATE BY SELECTIVE SIGMA(2) LIGANDS

It has now been accepted for several years that sigma (sigma) receptor s exist in, at least, two distinct entities denoted sigma(1) and sigma (2) Previous electrophysiological studies from our laboratory have dem onstrated that several selective sigma(1) ligands potentiate the neuro nal response to NMDA. The nonselective sigma(1)/sigma(2) ligand DTG al so potentiates the NMDA response, However, when DTG is administered at doses between 3 and 40 mu g/kg, the increase of NMDA-induced activati on turns to an epileptoid activity. Until recently, the physiological role of sigma(2) receptors had been less studied due to the lack of se lective sigma(2) ligands. The goal of the present electrophysiological studies was to assess the effect of the intravenous administration of new selective sigma(2) ligands on the neuronal response to NMDA in th e CA(3) region of the rat dorsal hippocampus. Lu 28-179 and ED 1008 po tentiated dose-dependently the NMDA response and generated bell-shaped dose-response curves, These ligands failed to generate any epileptoid activity an their own but the subsequent administration of a low dose of a sigma(1) agonist (JO-1784) induced an epileptoid activity. Inter estingly, the potentiations of the NMDA response induced by Lu 28-179 or ED 1008 were not reversed by haloperidol, by the neurosteroid proge sterone, nor by the selective sigma(1) antagonist NE-100, Ibogaine, a high affinity sigma(2) ligand, slightly increases the NMDA response, w hich was reversed by progesterone. These data suggest that, similarly to sigma(1) ligands, sigma(2) agonists potentiate the NMDA response an d that the coactivation of sigma(1) and sigma(2) receptors could be ne cessary to induce an epileptoid activity. They also suggest that halop eridol may not act as a sigma(2) antagonist and that several subtypes of sigma(2) receptors could exist. (C) 1998 Wiley-Liss, Inc.