It has now been accepted for several years that sigma () receptors exist in, at least, two distinct entities denoted 1 and 2 . Previous electrophysiological studies from our laboratory have demonstrated that several selective 1 ligands potentiate the neuronal response to NMDA. The nonselective 1 / 2 ligand DTG also potentiates the NMDA response. However, when DTG is administered at doses between 3 and 40 Β΅g/kg, the increase of NMDA-induced activation turns to an epileptoid activity. Until recently, the physiological role of 2 receptors had been less studied due to the lack of selective 2 ligands. The goal of the present electrophysiological studies was to assess the effect of the intravenous administration of new selective 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 doseresponse curves. These ligands failed to generate any epileptoid activity on their own but the subsequent administration of a low dose of a 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 1 antagonist NE-100. Ibogaine, a high affinity 2 ligand, slightly increases the NMDA response, which was reversed by progesterone. These data suggest that, similarly to 1 ligands, 2 agonists potentiate the NMDA response and that the coactivation of 1 and 2 receptors could be necessary to induce an epileptoid activity. They also suggest that haloperidol may not act as a 2 antagonist and that several subtypes of 2 receptors could exist.