There is growing preclinical evidence for the involvement of glutamate in the behavioral actions of nicotine. The aim of this study, was to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the cognitive and subjective effects of smoking in humans. Sixty regular smokers took part in this double-blind placebo controlled study, that investigated the effect of the NMDA-antagonist memantine (40 mg) and the nicotinic-receptor antagonist mecamylamine (10 mg) on smoking-induced improvement in performance of a task of sustained attention and on smoking-induced changes in subjective effects and craving. Increases in subjective ratings of 'buzzed' following smoking were reversed by memantine, but not by mecamylamine. In contrast, improvement on a Rapid Visual Information Processing task by smoking was opposed by mecamylamine, but not by memantine. Smoking reduced craving for cigarettes, but neither drug altered this effect. Our results suggest that glutamatergic mechanisms may have differential involvement in the subjective and cognitive actions of smoking. Further investigations using different ligands are warranted to fully characterize the role of glutamate underlying the consequences of smoking behavior. Keywords: smoking; memantine; mecamylamine; subjective; craving; cognition INTRODUCTIONNicotine is known to have positively reinforcing, subjective and cognitive effects (Stolerman and Jarvis, 1995;Levin et al, 2006). In humans, some of the measurable subjective effects of nicotine include 'buzzed', 'dizzy', 'stimulated' (Perkins et al, 1999) while positive cognitive effects include improvements in attention (Wesnes and Warburton, 1984) and memory (Rusted et al, 1998). The neurobiological mechanisms underlying these actions of nicotine are complex, involving not only a direct action of nicotine at receptors for acetylcholine, but also changes in release of other neurotransmitters, such as dopamine and glutamate (Watkins et al, 2000).Neurochemical studies have demonstrated that, at concentrations achieved during smoking, nicotine can enhance the release and function of glutamate, through an action at presynaptic receptors (eg McGehee et al, 1995). Such studies have determined that nicotine can alter glutamate release in several different areas of the brain, including the ventral tegmental area (Schilstrom et al, 1998(Schilstrom et al, , 2000Fu et al, 2000;Mansvelder and McGehee, 2000) the nucleus accumbens (Fu et al, 2000;Reid et al, 2000) the pre-frontal cortex (Toth et al, 1993;Vidal, 1994;Gioanni et al, 1999;) and the hippocampus (Gray et al, 1996;Radcliffe et al, 1999). These are areas thought to be involved in mediating the subjective (Rosecrans and Meltzer, 1981;Shoaib and Stolerman, 1992;Miyata et al, 1999) rewarding (Corrigall et al, 1994;Stolerman, 1996;Schroeder et al, 2001) and cognitive actions of nicotine (Stolerman, 1996;Levin et al, 1999).There is also growing evidence from behavioral models to indicate a role for glutamate in neurobiological mechanisms underlying the actions of nicotine....

Both compounds reduced latency for correct antisaccades, although neither reduced antisaccade errors. These findings are discussed with reference to the pharmacological route of performance enhancement on the antisaccade task and current models of antisaccade performance.