Glutamatergic Mechanisms in Cigarette Craving and Reward

描述（由申请人提供）：试图戒烟的吸烟者经常抱怨频繁和压倒性的吸烟渴望。事实上，烟瘾已被确定为烟草戒断综合征的一个突出特征，并经常被认为是戒烟治疗计划中观察到的高复吸率的主要原因。在研究烟瘾与戒烟治疗的关系的研究中，发现戒烟初期的烟瘾可能预示着短期和长期的治疗结果。与这些关于自然发生的渴望的研究平行，实验室研究发现，暗示诱导的香烟渴望和相关反应可预测随后参加戒烟计划的患者的复发。这些研究结果表明，香烟渴望，戒断和治疗结果之间有很强的关联。 临床前和临床研究表明，谷氨酸系统在药物滥用的急性和慢性效应中起着关键作用。动物研究表明，谷氨酸参与运动刺激，神经递质释放，致敏和奖励的影响，许多类别的药物滥用。最近的动物研究表明，尼古丁刺激谷氨酸释放，谷氨酸拮抗剂阻断尼古丁刺激的多巴胺释放和行为，并减少尼古丁戒断。在临床工作中，谷氨酸拮抗作用，无论是直接或间接，已被证明可以调节安非他明和可卡因的急性作用，减少阿片类药物和酒精戒断，并改善酒精和可卡因滥用的治疗结果。然而，很少有研究人员在尼古丁的临床研究中评估谷氨酸的药理学。 本研究将探讨药理学调制的香烟渴望和戒断寻求治疗的吸烟者，使用阿片类化合物。在药物治疗（8天）后，研究参与者将戒烟6小时，然后进行香烟提示反应性试验，然后对吸烟进行评价。测试的药物将包括临床上可用的化合物; dcycloserine（一种部分NMDA受体激动剂）0、50、100 mg/天和托吡酯（一种AMPA受体拮抗剂，具有神经元兴奋性减弱和GABA升高特性）0、75、150 mg/天。这些研究将采用3组、安慰剂对照、双盲研究设计进行。

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.