Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 3E1.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3101-6. doi: 10.1073/pnas.1114422109. Epub 2012 Jan 20.
Nicotine, the main psychoactive ingredient of tobacco smoke, induces negative motivational symptoms during withdrawal that contribute to relapse in dependent individuals. The neurobiological mechanisms underlying how the brain signals nicotine withdrawal remain poorly understood. Using electrophysiological, genetic, pharmacological, and behavioral methods, we demonstrate that tonic but not phasic activity is reduced during nicotine withdrawal in ventral tegmental area dopamine (DA) neurons, and that this pattern of signaling acts through DA D2 and adenosine A2A, but not DA D1, receptors. Selective blockade of phasic DA activity prevents the expression of conditioned place aversions to a single injection of nicotine in nondependent mice, but not to withdrawal from chronic nicotine in dependent mice, suggesting a shift from phasic to tonic dopaminergic mediation of the conditioned motivational response in nicotine dependent and withdrawn animals. Either increasing or decreasing activity at D2 or A2A receptors prevents the aversive motivational response to withdrawal from chronic nicotine, but not to acute nicotine. Modification of D1 receptor activity prevents the aversive response to acute nicotine, but not to nicotine withdrawal. This double dissociation demonstrates that the specific pattern of tonic DA activity at D2 receptors is a key mechanism in signaling the motivational effects experienced during nicotine withdrawal, and may represent a unique target for therapeutic treatments for nicotine addiction.
尼古丁是烟草烟雾中的主要精神活性成分，会在戒断期间引起负面的动机症状，导致依赖个体的复吸。大脑信号尼古丁戒断的神经生物学机制仍知之甚少。我们使用电生理学、遗传学、药理学和行为学方法，证明在腹侧被盖区多巴胺（DA）神经元中，尼古丁戒断期间的紧张但非突发活动减少，并且这种信号模式通过 DA D2 和腺苷 A2A 受体起作用，但不是 DA D1 受体。选择性阻断突发 DA 活动可预防单次尼古丁注射引起的非依赖小鼠的条件性位置厌恶表达，但不能预防依赖小鼠的慢性尼古丁戒断引起的条件性位置厌恶表达，这表明在尼古丁依赖和戒断动物中，条件性动机反应的多巴胺能传递从突发活动转向紧张活动。增加或减少 D2 或 A2A 受体的活动可预防慢性尼古丁戒断引起的厌恶动机反应，但不能预防急性尼古丁戒断引起的厌恶动机反应。D1 受体活性的改变可预防急性尼古丁引起的厌恶反应，但不能预防尼古丁戒断引起的厌恶反应。这种双重分离表明，D2 受体上紧张性 DA 活动的特定模式是信号尼古丁戒断期间所经历的动机效应的关键机制，可能代表尼古丁成瘾治疗的独特靶点。
