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Biphasic effects of sigma ligands on the neuronal response to N-methyl-D-aspartate

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Abstract

Previous studies from our laboratory have demonstrated that low doses of selective sigma (σ) 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 σ doses, the degree of potentiation induced by these two ligands progressively decreases (Bergeron et al. 1993). In the present experiments, the selective σ 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 μg/kg to 1 μg/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 σ 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 σ ligand. These two latter series of observations suggest that the lack of effect of the high doses of 6 ligands is not related to a rapid desensitisation of σ receptors. This biphasic effect of ligands might be due to the concomitant actions of these σ ligands on distinct subtypes of σ receptors.

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  1. Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, 1033 Pine Avenue West, H3A 1A1, Montreal, Quebec, Canada

    R. Bergeron, C. de Montigny & G. Debonnel

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  1. R. Bergeron
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  2. C. de Montigny
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  3. G. Debonnel
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Bergeron, R., de Montigny, C. & Debonnel, G. Biphasic effects of sigma ligands on the neuronal response to N-methyl-D-aspartate. Naunyn-Schmiedeberg's Arch Pharmacol 351, 252–260 (1995). https://doi.org/10.1007/BF00233244

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