Glutamatergic Mechanisms in Cigarette Craving and Reward

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DESCRIPTION (provided by applicant): Cigarette smokers attempting to quit often complain of frequent and overwhelming periods of cigarette craving. Indeed, craving has been identified as a prominent feature of the tobacco withdrawal syndrome and is frequently suggested to be a major contributor to the high rate of relapse observed in smoking cessation treatment programs. In studies examining the relationship of craving with smoking cessation treatment, findings show that cigarette craving during the initial period of abstinence may be predictive of both short and long term treatment outcome. In parallel with these studies on naturally occurring craving, laboratory studies have found that cue-induced cigarette craving and related responses are predictive of relapse in patients that are subsequently enrolled into smoking cessation programs. These findings indicate a strong association between cigarette craving, withdrawal and therapeutic outcome. Pre-clinical and clinical studies have indicated that glutamate systems play a critical role in the acute and chronic effects of drugs of abuse. Animal studies have demonstrated glutamate involvement in the locomotor stimulatory, neurotransmitter release, sensitization, and rewarding effects of numerous classes of drugs of abuse. Recent animal studies have demonstrated nicotine stimulation of glutamate release and that glutamate antagonists block nicotine stimulated dopamine release and behavior, and reduce nicotine withdrawal. In clinical work, glutamate antagonism, either direct or indirect, has been shown to modulate the acute effects of amphetamine and cocaine, to reduce opiate and alcohol withdrawal, and to improve alcohol and cocaine abuse treatment outcome. Few investigators, however, have evaluated glutamate pharmacology in clinical studies on nicotine. This study will examine pharmacological modulation of cigarette craving and withdrawal in treatment seeking cigarette smokers, using glutamatergic compounds. Following medication treatment (8 days), study participants will abstain from smoking for 6 hours and then undergo cigarette cue reactivity tests followed by the evaluation of a smoked cigarette. Medications tested will include clinically available compounds; dcycloserine (a partial NMDA receptor agonist) at 0, 50, 100 mg/day and topiramate (an AMPA receptor antagonist with neuron excitability attenuating and GABA elevating properties) at 0, 75, 150 mg/day. These investigations will be performed using a 3-armed, placebo controlled, double-blind study design.