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Nicotine administration stimulates the in vivo N‐methyl‐ D ‐aspartate receptor/nitric oxide/cyclic GMP pathway in rat hippocampus through glutamate release
Author(s) -
Fedele Ernesto,
Varnier Giorgia,
Antonia Ansaldo Maria,
Raiteri Maurizio
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702130
Subject(s) - mecamylamine , nicotine , nmda receptor , microdialysis , soluble guanylyl cyclase , dizocilpine , chemistry , pharmacology , nitroarginine , nitric oxide , nitric oxide synthase , medicine , endocrinology , nicotinic agonist , extracellular , receptor , biochemistry , guanylate cyclase
1 The in vivo effects 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 effect 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 outflow also when administered directly into the hippocampus; the effect 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 outflows of γ‐aminobutyric acid (GABA) and glycine remained unaffected. Following local administration of high concentrations of nicotine, animals displayed symptoms of mild excitation (sniffing, increased motor and exploratory activity) during the first 20–40 min of infusion, followed by wet dog shake episodes; these behavioural effects 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.British Journal of Pharmacology (1998) 125 , 1042–1048; doi: 10.1038/sj.bjp.0702130