Cigarette smoking is a pernicious national and global public health problem.1, 2 Nearly 50 million Americans smoke cigarettes despite widely publicized and acknowledged health warnings and restrictions on public smoking. Smoking has been branded as the most important preventable cause of all deaths in the United States (US), and 45% of smokers will die of tobacco related disorders.3, 4 Tobacco dependence is mediated, in part, by the reinforcing effects of nicotine.5 According to the US Public Health Service Clinical Practice Guideline, Treating Tobacco Use and Dependence, every patient attempting to stop smoking should be offered pharmacotherapy for smoking cessation.6 Pharmacological treatment strategies have included nicotine replacement therapy (NRT (nicotine formulations)), antagonist therapy (mecamylamine), therapies to make nicotine intake aversive (silver acetate), non-nicotine medications that mimic some of nicotine's neurophysiological effects (antidepressants), and medications to block craving and withdrawal symptoms (nicotine formulations, antidepressants, clonidine). A number of drug therapies for smoking cessation have demonstrated some efficacy in facilitating smoking cessation. These include NRT using a variety of nicotine formulations (e.g., pill, gum, patch, etc.);7-14 combined nicotine replacement and mecamylamine;15 the antidepressants, bupropion SR,16-19 nortriptyline,19-21 doxepin,22 and fluoxetine;23, 24 the alpha2 agonist, clonidine;25-27 and the anxiolytic, buspirone.28 Among these agents, first-line pharmacotherapies approved by the US Food and Drug Administration (FDA) that include bupropion SR and various NRT products have been found to approximately double long-term abstinence rates compared with placebo.29-31 However, roughly 7 to 8 out of 10 individuals who use these medications do not achieve long-term abstinence. I n addition to the limitations of currently available treatments for smoking cessation, several other clinical factors complicate the treatment of nicotine dependence. First, patients with a history of major depressive disorder appear to have a lower likelihood of achieving sustained smoking abstinence and an increased risk of depressive symptom emergence than patients without a history of major depressive disorder.32-44 Second, the emergence of prominent mood symptoms associated with nicotine withdrawal (e.g., anxiety, dysphoric or depressed mood, insomnia, irritability, and restlessness) reduce the likelihood of abstinence.35, 37, 44 Third, appetite increases and weight gain are also components of nicotine withdrawal and have negative health consequences.30, 45 Activation of the mesocorticolimbic dopamine (DA) system has been implicated in the reinforcing and dependence-producing effects of nicotine.46, 47 However, attempts to ameliorate the symptoms of nicotine dependence/withdrawal using DA receptors as therapeutic targets has met with only modest success.48, 49 Recent studies in rodents suggest that glutamatergic activation of N-methyl-D-aspartate (NMDA) receptors within the ventral tegmentum (VT) may be needed for nicotine to stimulate dopamine release in the nucleus accumbens.50-52 These findings are consistent with the reduction of nicotine-induced increases in locomotor activity observed with microinfusion of ionotropic glutamate receptor antagonists.53, 54 Thus, agents that indirectly modulate dopaminergic neurotransmission in the mesocorticolimbic reward circuit via their effects on presynaptic glutamatergic inputs to these dopamine neurons offer promise as novel adjuvants in the treatment of nicotine addiction.