根据7月27日发表在《The Journal of Neuroscience》上的一项新的动物研究，消除位于大脑奖赏中心的细胞中的一个蛋白质，可阻断焦虑和减轻尼古丁的奖赏效应，这一发现可能有助于研究人员更好地了解尼古丁如何影响大脑。
尼古丁通过结合脑细胞表面的称之为烟碱受体的蛋白质而起作用。在新研究中，由Salk生物研究所的Tresa McGranahan、StePHen Heinemann博士、T. K. Booker博士领导的研究人员发现，从产生多巴胺的脑细胞中去除一种特殊类型的烟碱受体，可使小鼠不太可能找到尼古丁。多巴胺是一种响应奖励的化学物质。小鼠并未显示出尼古丁治疗后常见的焦虑样行为的减少。吸烟者常报告的焦虑缓解是持续吸烟或复发的关键因素。
“这些发现表明了被认为在烟草成瘾的发展中起到了关键作用的尼古丁奖励和减轻焦虑的性质与一组脑细胞的活动有关，”Scripps研究所药物成瘾专家 Paul Kenny博士说，而他未加入该研究。
以往的研究表明，阻断腹侧被盖区（VTA）的alPHa4烟碱受体，可削弱尼古丁的奖励的性质，VTA是一个重要的大脑区域，与动机、情感和成瘾有关。由于alPHa4受体存在于腹侧被盖区的若干类细胞上，目前还不清楚尼古丁是如何产生愉悦感的。
为了研究大脑中对尼古丁反应的重要通路，研究人员开发了一种无法产生alpha4受体的基因突变小鼠，但仅限于多巴胺脑细胞。与正常小鼠相比，这些细胞中缺乏alpha4受体的小鼠可花费更少的时间获得尼古丁。这表明alpha4受体对于尼古丁的奖赏效应是必需的。尼古丁也没能减少突变小鼠的焦虑行为，而它通常在健康小鼠可起作用。
McGranahan说：“确认对尼古丁成瘾的两个主要特征-奖励和焦虑是必需的烟碱受体的种类，将可能有助于我们更好地理解导致尼古丁依赖的途径，以及对全球十亿吸烟者潜在的治疗方法”。与烟草使用相关的疾病仍然是全球的主要杀手，每年造成500多万人死亡。
这一发现可引导研究人员更好地理解烟草成瘾的机制，并协助开发新的药物来治疗烟瘾，并可缓解焦虑症，Kenny补充说。
这项研究获得了国家神经疾病与中风研究所、美国国家酒精滥用和酒精中毒研究所，国家药物滥用研究所的支持。(生物谷 Bioon.com)
doi:10.1523/?JNEUROSCI.0937-11.2011
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α4β2 Nicotinic Acetylcholine Receptors on Dopaminergic Neurons Mediate Nicotine Reward and Anxiety Relief
Tresa M. McGranahan, Natalie E. Patzlaff, Sharon R. Grady, Stephen F. Heinemann, and T. K. Booker
Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors.
