Glutamatergic Mechanisms in Cigarette Craving and Reward

描述(申请人提供)：试图戒烟的吸烟者经常抱怨频繁和强烈的烟瘾。事实上，渴求已被确定为烟草戒断综合征的一个显著特征，并经常被认为是戒烟治疗方案中观察到的高复发率的主要原因。在研究渴望与戒烟治疗的关系的研究中，研究结果表明，戒烟初期的渴望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同时，实验室研究发现，线索诱导的香烟渴望和相关反应可以预测随后加入戒烟计划的患者的复发。这些发现表明，吸烟渴望、戒烟和治疗结果之间存在很强的关联。 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影响中发挥着关键作用。动物研究表明，谷氨酸参与了多种滥用药物的运动刺激、神经递质释放、敏化和奖赏效应。最近的动物研究表明，尼古丁刺激谷氨酸的释放，谷氨酸拮抗剂阻断尼古丁刺激的多巴胺释放和行为，并减少尼古丁的戒断。在临床工作中，谷氨酸拮抗作用，无论是直接的还是间接的，都被证明可以调节安非他明和可卡因的急性效应，减少阿片和酒精的戒断，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作用。 这项研究将使用谷氨酸能化合物来研究寻求吸烟的吸烟者在治疗过程中对香烟渴望和戒断的药理调节。在药物治疗(8天)之后，研究参与者将戒烟6小时，然后接受香烟线索反应性测试，然后评估吸烟的情况。测试的药物将包括临床上可用的化合物；双环丝氨酸(一种部分NMDA受体激动剂)，每天0、50、100毫克；托吡酯(一种AMPA受体拮抗剂，具有减弱神经元兴奋性和提高GABA的特性)，每天0、75、150毫克。这些研究将采用三臂、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.