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 CA3 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 micrograms/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 CA3 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 sigma ligands is not related to a rapid desensitisation of sigma receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Bergeron
R
R
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
de Montigny
C
C
Debonnel
G
G
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007275:Injections, Intravenous; D007478:Iontophoresis; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*
D008024:Ligands; D017480:Receptors, sigma; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D000109:Acetylcholine