Differential Involvement of Glutamatergic Mechanisms in the Cognitive and Subjective Effects of Smoking

Abstract

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....

Cue exposure and response prevention with heavy smokers: a laboratory-based randomised placebo-controlled trial examining the effects of D-cycloserine on cue reactivity and attentional bias

“…reduced euphoria following DCS, compared to increased euphoria in Kamboj et al 2011), possibly implicating glutamatergic regulation of affect under conditions of nicotine deprivation (cf. Jackson et al 2009;Nesic et al 2011). …”

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal

“…A recent meta-analysis concluded that memantine improved cognition and clinician’s global impression in patients with Alzheimer’s disease [60]. Although it is not clear whether memantine improves cognitive performance in healthy adults [61], memantine attenuated nicotine self-administration in rats [62] and decreased the subjective effects of cigarette smoking in adult smokers [63]. Another study found no effect of memantine on cognition or smoking behaviour [63].…”

“…Although it is not clear whether memantine improves cognitive performance in healthy adults [61], memantine attenuated nicotine self-administration in rats [62] and decreased the subjective effects of cigarette smoking in adult smokers [63]. Another study found no effect of memantine on cognition or smoking behaviour [63]. There is also evidence that combined treatment of memantine and AChEIs may be more effective at reducing cognitive decline in Alzheimer’s patients [64].…”

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