Benzodiazepine-sensitive GABA(A) receptors limit the activity of the NMDA/NO/cyclic GMP pathway: a microdialysis study in the cerebellum of freely moving rats.
In the cerebellum, infusion of NMDA (200 microM) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABA(A) receptor agonist muscimol (0.01-100 microM) was able to counteract the NMDA effect with an EC(50) of 0.65 microM; the inhibitory effect of muscimol (10 microM) was prevented by bicuculline (50 microM). Diazepam (10 microM) significantly potentiated the muscimol (1 microM) inhibition; furthermore, when coinfused with 0.1 microM muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 microM) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 microM). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 microM), together with muscimol and diazepam, almost completely restored the effect of NMDA on extracellular cGMP levels. It is concluded that GABA(A) receptors potently control the NMDA/nitric oxide/cGMP pathway in the cerebellum in vivo. In terms of the alpha subunit composition, we can deduce that the cerebellar GABA(A) receptor does not contain alpha(6) or beta(4) 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 alpha(5) subunits in the receptor composition and suggest the involvement of an alpha(1) subunit.
Fedele
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Sezione di Farmacologia e Tossicologia, Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy.
Ansaldo
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MA
Varnier
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Raiteri
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D017551:Microdialysis / Q000379:methods; D009118:Muscimol / Q000494:pharmacology; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D011725:Pyridines; D011963:Receptors, GABA-A; D009118:Muscimol; D005442:Flumazenil; D016202:N-Methylaspartate; D000077334:Zolpidem; D006152:Cyclic GMP; D003975:Diazepam; D001640:Bicuculline