吸烟在美国和其他发达国家是头号可预防的致死因素，吸烟可导致肺癌，心脏病和慢性支气管炎，但平均来讲吸烟者一般都比不吸烟者瘦。最新一期Science中，一项研究揭示了尼古丁----香烟中的活性成分是如何通过作用于大脑抑制吸烟者食欲的，同时该研究还定位了一个新的戒烟和减肥的药物作用靶点。
人脑中尼古丁受体包括15个亚单位，它们可通过多种方式组合形成具有不同功能的受体。尼古丁可与其中任意一种受体相结合进而激发一系列反应：一些可导致香烟成瘾，另一些则可导致血压升高或产生放松感。很久以前人们就已经了解到尼古丁可导致食欲下降，科学家们怀疑这种现象与奖赏和行为强化相关受体有关，毕竟，大脑把香烟和食物都当作奖赏，但新发现证实食欲有属于自己的通路。
耶鲁大学行为神经科学专家Marina Picciotto本打算研究是否激活尼古丁受体α3β4对小鼠有抗抑郁作用。但她的博士后Yann Mineur在观察α3β4受体激活小鼠时，发现小鼠食量明显减少
Picciotto表示：在此研究之前，我们真的不知道大脑中的这种受体在食物摄取方面有如此大的作用。她和Mineur进一步证实尼古丁与 α3β4 受体结合之后可向大脑发出过饱的信号，这种信号和吃了一顿大餐后大脑发出的信号无异。研究小组在8日刊出的Science杂志中称：小鼠在使用 α3β4 受体结合剂2小时后，食欲仅为对照组的一半。它们体内脂肪含量在30天时下降15-20%
由于戒烟后的体重增长常常成为吸烟者戒烟的障碍，Picciotto建议药企关注她发现的通路，以达到戒烟初期抑制食欲的目的。这种药物还有更广泛的应用，可作为食欲抑制剂帮助减肥，且不会产生吸烟相关性危害
马里兰州Bethesda市Uniformed Services University of the Health Sciences大学的行为神经科学专家Neil Grunberg首次通过小鼠在1982年证实尼古丁可引起食欲下降，他说这项新研究在理解他的发现方面迈进了一步
Grunberg说：多数人已接受食欲下降与多巴胺奖赏通路有关并暂时停止了争论，我认为这项研究最重要的贡献是证实了另外存在一条尼古丁作用通路
但Grunberg指出该研究只对雄性小鼠进行了研究。在早期研究中，他曾发现尼古丁对体重的影响在雄性和雌性小鼠间存在差异。他说，雌性小鼠在开始吸烟和戒烟后的体重变化幅度都大于雄性小鼠。是否这意味着在雌性大脑中尼古丁通过另外一条激素调控通路发挥作用还不得而知
Picciotto称她的小组正对雌性小鼠进行重复实验，她说：我们也正在试图回到开始的问题，是否这种受体也有抗抑郁的作用？
吸烟者“骷髅”图
生物探索推荐英文原文
Why Smokers Are Skinny
Craving an afternoon snack? Take a drag on a cigarette, and your hunger will likely disappear. Smoking is the number one cause of preventable deaths in the Unites States and other developed countries, causing lung cancer, heart disease, and chronic bronchitis. But smokers are, on average, skinnier than nonsmokers. New research reveals how nicotine, the active ingredient in cigarettes, works in the brain to suppress smokers' appetites. The finding also pinpoints a new drug target for nicotine withdrawal—and weight loss.
The nicotine receptor in the brain has 15 subunits; they can combine in a multitude of ways to form different receptors with different jobs. Nicotine can bind to each combination and spur a cascade of distinct events; some lead to the addictive properties of cigarettes, others to an increase in blood pressure or a feeling of relaxation. It's long been known that nicotine causes a slump in appetite, and scientists suspected that this worked through receptors associated with reward and behavior reinforcement. After all, the brain considers both cigarettes and food to be rewards. But the new finding suggests that appetite has its own pathway.
Behavioral neuroscientist Marina Picciotto of Yale University set out to study whether activating one particular nicotine receptor, dubbed α3β4, had antidepressant effects on mice. But as postdoctoral researcher Yann Mineur was caring for the mice, which had received drugs engineered to stimulate only α3β4 receptors, he noticed a side effect: the mice were eating less.
"Before this study, we really didn't think that this type of receptor would have such a big role in the brain in food intake," Picciotto says. She and Mineur went on to show that nicotine does, in fact, bind to α3β4 receptors, which then send a signal throughout the rest of the brain, signaling satiety. It's indistinguishable from the signal the brain propagates after eating a large meal. Mice that received the drug binding to the α3β4 receptor ate half the amount of food as untreated mice in the 2 hours following administration of the drug. Their body fat dropped 15% to 20% over 30 days, the team reports online today in Science.
Since the weight gain that comes with stopping smoking is often one deterrent for smokers to quit, Picciotto suggests that the new pathway could be targeted by pharmaceuticals to suppress appetite during the initial stages of smoking cessation. In addition, such a drug could have wider reach as an appetite suppressant to aid in weight loss, without the health hazards tied to cigarette smoke.
Neil Grunberg, a behavioral neuroscientist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, was the first to prove, through rat studies in 1982, that nicotine causes a decrease in appetite. He says the new study is a step forward in understanding the phenomenon he first observed.
"Most people had accepted that the decrease in appetite was caused through a dopamine-reward pathway and left it at that," Grunberg says. "So I think the most important contribution of this paper is to prove that there is another whole pathway that nicotine is working through."
Grunberg notes, however, that the study looks only at male mice. In his previous work, he has found differences in the effects of nicotine on weight between males and females. Females, he says, experience larger weight loss when they start smoking and a larger weight gain if they quit. Whether this means nicotine is working through an additional, hormone-regulated pathway in the female brain is yet to be determined.
Picciotto says her group is repeating the experiments on female mice. "We're also still trying to get back to that original question we had," she says: "Does this also have antidepressant actions?"
