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 (σ) receptors exist in, at least, two distinct entities denoted σ 1 and σ 2 . Previous electrophysiological studies from our laboratory have demonstrated that several selective σ 1 ligands potentiate the neuronal response to NMDA. The nonselective σ 1 /σ 2 ligand DTG also potentiates the NMDA response. However, when DTG is administered at doses between 3 and 40 μg/kg, the increase of NMDA‐induced activation turns to an epileptoid activity. Until recently, the physiological role of σ 2 receptors had been less studied due to the lack of selective σ 2 ligands. The goal of the present electrophysiological studies was to assess the effect of the intravenous administration of new selective σ 2 ligands on the neuronal response to NMDA in the CA 3 region of the rat dorsal hippocampus. Lu 28‐179 and BD 1008 potentiated dose‐dependently the NMDA response and generated bell‐shaped dose‐response curves. These ligands failed to generate any epileptoid activity on their own but the subsequent administration of a low dose of a σ 1 agonist (JO‐1784) induced an epileptoid activity. Interestingly, the potentiations of the NMDA response induced by Lu 28‐179 or BD 1008 were not reversed by haloperidol, by the neurosteroid progesterone, nor by the selective σ 1 antagonist NE‐100. Ibogaine, a high affinity σ 2 ligand, slightly increases the NMDA response, which was reversed by progesterone. These data suggest that, similarly to σ 1 ligands, σ 2 agonists potentiate the NMDA response and that the coactivation of σ 1 and σ 2 receptors could be necessary to induce an epileptoid activity. They also suggest that haloperidol may not act as a σ 2 antagonist and that several subtypes of σ 2 receptors could exist. Synapse 29:62–71, 1998. © 1998 Wiley‐Liss, Inc.