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Modulation by sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency

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Summary

The effects of the high affinity sigma (σ) ligands 1,3-di(2-tolyl)guanidine (DTG), (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), (+)3-[3-hydroxyphenyl]N-(1-propyl)piperidine hydrochloride [(+)3-PPP] and haloperidol were studied on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline (NA) from preloaded hippocampal slices made from SpragueDawley rats. The [3H]NA release was evoked once by a 4 min exposure to NMDA, 40 min after the beginning of superfusion with a Mg -free Krebs' solution. In the absence of any drug, NMDA evoked a concentration-dependent [3H]NA release. Mg++ and EGTA abolished the [3H]NA release induced by NMDA. JO-1784 and (+)3-PPP potentiated in a concentration-dependent manner NMDA-induced [3H]NA release, without affecting the basal outflow. DTG concentration-dependently inhibited the overflow of [3H]NA evoked by NMDA, without affecting the basal efflux. Haloperidol, which did not modify NMDA-evoked [3H]NA release by itself, completely prevented the effects of JO-1784, (+)3-PPP and DTG. In contrast, spiperone, also a potent dopamine receptor antagonist but with low affinity for (σ) binding sites, failed to prevent the potentiation of NMDA-evoked release of [3H]NA by JO-1784 and (+)3-PPP The possible involvement of Gi/o proteins in the modulation by (σ) ligands of NMDA evoked [3H]NA release in the rat hippocampus was also investigated. To this end, Gi/o proteins were inactivated with pertussis toxin (PTX), injected locally 3 to 11 days prior to the experiment or with in vitro preincubation with N-ethylmaleimide (NEM) for 30 min prior the experiment. Both the in vivo PTX and the in vitro NEM pretreatments abolished the potentiating effects of JO-1784 and (+)3-PPP, and shifted the concentration-effect curve for DTG-induced suppression of NMDA-evoked release of [3H]NA to the right. These results suggest that the (σ) receptors mediating the effects of JO-1784, (+)3-PPP and DTG on NMDA-evoked release of [3H]NA are coupled to Gi/o proteins.

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Authors and Affiliations

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

    François P. Monnet, Pierre Blier, Guy Debonnel & Claude de Montigny

  2. Jouveinal Research Institute, 7 Allée des Jachères, Cédex 423, F-94263, Fresnes, France

    François P. Monnet

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  1. François P. Monnet
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Monnet, F.P., Blier, P., Debonnel, G. et al. Modulation by sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency. Naunyn-Schmiedeberg's Arch Pharmacol 346, 32–39 (1992). https://doi.org/10.1007/BF00167567

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