1 The in vivo e ects of nicotine on the nitric oxide (NO) synthase/cyclic GMP pathway of the adult rat hippocampus have been investigated by monitoring the levels of extracellular cyclic GMP during microdialysis in conscious unrestrained animals. 2 Intraperitoneal (i.p.) administration of nicotine caused elevation of cyclic GMP levels which was prevented by mecamylamine. The e ect of nicotine was abolished by local infusion of the NO synthase inhibitor N G -nitro-L-arginine (L-NOARG) or by the soluble guanylyl cyclase blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). 3 Local administration of the NMDA receptor antagonists cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS19755) and dizocilpine (MK-801) inhibited by about 60% the nicotine-induced elevation of cyclic GMP. Nicotine was able to stimulate cyclic GMP out¯ow also when administered directly into the hippocampus; the e ect was sensitive to mecamylamine, L-NOARG, ODQ or MK-801. 4 Nicotine, either administered i.p. or infused locally, produced augmentation of glutamate and aspartate extracellular levels, whereas the out¯ows of g-aminobutyric acid (GABA) and glycine remained una ected. Following local administration of high concentrations of nicotine, animals displayed symptoms of mild excitation (sni ng, increased motor and exploratory activity) during the ®rst 20 ± 40 min of infusion, followed by wet dog shake episodes; these behavioural e ects were prevented by mecamylamine or MK-801, but not by L-NOARG or by ODQ. 5 It is concluded that (a) nicotine stimulates the production of NO and cyclic GMP in the hippocampus; (b) this occurs, at least in part, through release of glutamate/aspartate and activation of NMDA receptors. Modulation of the NMDA receptor/NO synthase/cyclic GMP pathway may be involved in the cognitive activities of nicotine.

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Abstract:In the cerebellum, infusion of NMDA (200 M ) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABA A receptor agonist muscimol (0.01-100 M ) was able to counteract the NMDA effect with an EC 50 of 0.65 M; the inhibitory effect of muscimol (10 M ) was prevented by bicuculline (50 M ). Diazepam (10 M ) significantly potentiated the muscimol (1 M ) inhibition; furthermore, when coinfused with 0.1 M muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 M ) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 M ). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 M ), 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 ␣ subunit composition, we can deduce that the cerebellar GABA A receptor does not contain ␣ 6 or ␣ 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 ␣ 5 subunits in the receptor composition and suggest the involvement of an ␣ 1 subunit. Key Words: GABA receptorsBenzodiazepines-NMDA/nitric oxide/cyclic GMP pathway-Microdialysis-Cerebellum. J. Neurochem. 75, 782-787 (2000).Abundant studies have indicated that abnormal excitatory neurotransmission, especially through NMDA receptors, underlies neurodegenerative processes that characterize several acute and chronic pathologies. In particular, great interest has emerged with regard to nitric oxide (NO) as it has been shown that, among other harmful chemical species, this gaseous molecule is responsible for NMDA receptor-mediated cell injury

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