Modulation of the neuronal response to N-methyl-D-aspartate by selective sigma2 ligands.
It has now been accepted for several years that sigma (sigma) receptors exist in, at least, two distinct entities denoted sigma1 and sigma2. Previous electrophysiological studies from our laboratory have demonstrated that several selective sigma1 ligands potentiate the neuronal response to NMDA. The nonselective sigma1/sigma2 ligand DTG also potentiates the NMDA response. However, when DTG is administered at doses between 3 and 40 microg/kg, the increase of NMDA-induced activation turns to an epileptoid activity. Until recently, the physiological role of sigma2 receptors had been less studied due to the lack of selective sigma2 ligands. The goal of the present electrophysiological studies was to assess the effect of the intravenous administration of new selective sigma2 ligands on the neuronal response to NMDA in the CA3 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 sigma1 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 sigma1 antagonist NE-100. Ibogaine, a high affinity sigma2 ligand, slightly increases the NMDA response, which was reversed by progesterone. These data suggest that, similarly to sigma1 ligands, sigma2 agonists potentiate the NMDA response and that the coactivation of sigma1 and sigma2 receptors could be necessary to induce an epileptoid activity. They also suggest that haloperidol may not act as a sigma2 antagonist and that several subtypes of sigma2 receptors could exist.
Couture
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Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada.
Debonnel
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D000818:Animals; D004594:Electrophysiology; D005021:Ethylamines / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007050:Ibogaine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology
D005021:Ethylamines; D007211:Indoles; D008024:Ligands; C109644:Lu 28-179; D011759:Pyrrolidines; D017480:Receptors, sigma; D013141:Spiro Compounds; C085527:BD 1008; D007050:Ibogaine; D016202:N-Methylaspartate