NICOTINE ADMINISTRATION STIMULATES THE IN-VIVO N-METHYL-D-ASPARTATE RECEPTOR NITRIC OXIDE/CYCLIC GMP PATHWAY IN RAT HIPPOCAMPUS THROUGH GLUTAMATE RELEASE/

1 The in vivo effects of nicotine on the nitric oxide (NO) synthase/cy clic GMP pathway of the adult rat hippocampus have been investigated b y monitoring the levels of extracellular cyclic GMP during microdialys is in conscious unrestrained animals. 2 Intraperitoneal (i.p.) adminis tration of nicotine caused elevation of cyclic GMP levels which was pr evented 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 a ntagonists cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid (GGS197 55) and dizocilpine (MK-801) inhibited by about 60% the nicotine-induc ed elevation of cyclic GMP. Nicotine was able to stimulate cyclic CMP outflow also when administered directly into the hippocampus; the effe ct 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 gamma-aminobutyric acid (GABA) and glycine remained unaffected. Follow ing local administration of high concentrations of nicotine, animals d isplayed symptoms of mild excitation (sniffing, increased motor and ex ploratory activity) during the first 20-40 min of infusion, followed b y 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 conclude d that (a) nicotine stimulates the production of NO and cyclic CMP in the hippocampus; (b) this occurs, at least in part, through release of glutamate/aspartate and activation of NMDA receptors. Modulation of t he NMDA receptor/NO synthase/cyclic CMP pathway may be involved in the cognitive activities of nicotine.