Benzodiazepine-Sensitive GABAA Receptors Limit the Activity of the NMDA/NO/Cyclic GMP Pathway

A Microdialysis Study in the Cerebellum of Freely Moving Rats

Authors


  • Abbreviations used : cGMP, cyclic GMP ; NO, nitric oxide ; NOS, nitric oxide synthase.

Address correspondence and reprint requests to Dr. M. Raiteri at Sezione di Farmacologia e Tossicologia, Dipartimento di Medicina Sperimentale, Università di Genova, Viale Cembrano 4, 16148 Genova, Italy. E-mail : raiteri@pharmatox.unige.it

Abstract

In the cerebellum, infusion of NMDA (200 μM) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABAA receptor agonist muscimol (0.01-100 μM) was able to counteract the NMDA effect with an EC50 of 0.65 μM ; the inhibitory effect of muscimol (10 μM) was prevented by bicuculline (50 μM). Diazepam (10 μM) significantly potentiated the muscimol (1 μM) inhibition ; furthermore, when coinfused with 0.1 μM muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 μM) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 μM). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 μM), together with muscimol and diazepam, almost completely restored the effect of NMDA on extracellular cGMP levels. It is concluded that GABAA receptors potently control the NMDA/nitric oxide/cGMP pathway in the cerebellum in vivo. In terms of the α subunit composition, we can deduce that the cerebellar GABAA receptor does not contain α6 or β4 subunits because it is diazepam-sensitive. Moreover, the observation that zolpidem is active at a rather low concentration, in combination with localization studies present in the literature, tend to exclude the presence of α5 subunits in the receptor composition and suggest the involvement of an α1 subunit.

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