一瘾难禁：尼古丁上瘾机制的最新发现 [美国媒体]

SO HARD TO QUIT: NEW MECHANISM IN NICOTINE ADDICTION DISCOVERED

一瘾难禁：尼古丁上瘾机制的最新发现

Part of the reason people find smoking difficult to quit is that each time they have a cigarette, feelings of craving, irritability and anxiety melt away. This component of addiction is known as negative reward and is controlled in part by a region of the brain called the habenula. The neurotransmitters acetylcholine and glutamate are thought to influence nicotine dependence in the habenula, but the molecular details of this regulation are unclear.

烟之所以难戒，其中一大原因就是给戒烟的人一支烟后，那种百爪挠心、邪火上涌、躁动不安的感觉就像烈日融雪般消失不见了。我们早已知道，上瘾后的这种表现叫做负反馈，是受大脑缰核（Habenula，Hb）控制的。而神经递质乙酰胆碱和谷氨酸也可以影响缰核的尼古丁依赖症状，但这其中的具体机理还有待研究。

“We knew that both of these neurotransmitters played important roles in the neurons in the habenula,” says Ines Ibanez-Tallon, Research Associate Professor in the Laboratory of Molecular Biology, headed by James and Marilyn Simons Professor Nathaniel Heintz. “What we didn’t know was how they might interact, or work together to reinforce addiction.”

“已知这些神经递质对缰核神经元都有很大影响，”Ines Ibanez-Tallon分子生物学实验室的研究副教授，该实验室的领头人是获享James and Marilyn Simons基金资助的Nathaniel Heintz教授，“而我们想搞清楚的就是它们之间到底是怎么分工，亦或是合作来增强上瘾症状的。”

Ibanez-Tallon and colleagues now report that acetylcholine regulates glutamate signaling in the habenula, identifying a new mechanism important for nicotine dependence. The study was published on December 1 in eLife.

Ibanez-Tallon及其同事的报告指出乙酰胆碱调节缰核中的谷氨酸信号，以此揭示了尼古丁依赖的最新重要机制。该研究成果被发表在12月1日的《eLife》上。

Neurotransmitter control

神经递质控制

Neurotransmitters, the chemical messengers of the brain, are packaged into spherical structures called vesicles, which reside at the ends of neurons. Upon receiving certain signals, neurons release their vesicle contents into the synapse, perpetuating the signal onto the next neuron. Neurons can recycle neurotransmitters by reabsorbing them through reuptake, a process that allows them to precisely control the amounts of neurotransmitters in the synapse.

神经递质是脑内的一种化学信使，储存在神经元末梢的球形小囊里。一旦收到脑发出的指令，神经元就会释放小囊里的各种成分。这些成分被释放后就到了神经突触中，神经突触再将信号传给下一个神经元，同样的机制在下一个神经元中再次重现，如此便保证了信号的持续传播。而且这些神经递质是可以被重复利用的，神经元能将释放了的神经递质再重新吸收回来，这个过程被称为再摄取（reuptake），再摄取使得神经元能够精确地控制神经突触中神经递质的总量。

Even a small upset in the balance of neurotransmitters can result in altered behavior. In the case of acetylcholine, it can influence our ability to cope with addiction.

神经递质的平衡即使只是被小小地搅乱一下，也会造成完全不同的后果。对于乙酰胆碱来说，它可以影响我们对抗上瘾症的能力。

“To understand how these neurotransmitters work, we created a mouse model whose habenular neurons don’t make acetylcholine because the mice lack a key gene involved in acetylcholine processing,” says Ibanez-Tallon. “In our experiments, we observed that the elimination of acetylcholine affected glutamate in this brain region in two ways. First, the amount of glutamate released by neurons was reduced. And second, the reuptake of glutamate back into vesicles was impaired. Both of these mechanisms affect the excitability of neurons, meaning normal signaling is disrupted.”

“为了理解这些神经递质到底是怎么工作的，我们创造了一种特殊的老鼠来作为实验模型，这种老鼠缺少一种关键的基因，因此它们的缰核神经元是无法制造乙酰胆碱的，”Ibanez-Tallon说，“我们在实验中观察到，由于消除了乙酰胆碱，在脑部这一区域的谷氨酸受到了两种影响。第一，神经元释放的谷氨酸总量少了。第二，谷氨酸的再摄取不能正常进行。这两种机制都对神经元的兴奋度产生了影响，即神经信号的传递被打断了。”

Based on these findings, the researchers suggest that acetylcholine regulates how much glutamate is released into the synapse, and at what frequency. It also facilitates the packaging of glutamate into vesicles.

基于他们的实验结果，研究者认为乙酰胆碱可以调节谷氨酸在神经突触中的释放量以及释放频率。并且还加快了谷氨酸被打包进小囊的过程。



The neurotransmitters acetylcholine and glutamate were known to play a role in nicotine dependence. The orange region above shows the overlap of these neurotransmitters in the habenular circuit, where they interact to reinforce addiction. Credit: Laboratory of Molecular Biology at The Rockefeller University.

神经递质乙酰胆碱和谷氨酸在尼古丁依赖中起到了重要作用。上图中桔色的区域显示了这些神经递质不断在缰核中重复释放，此相互作用增强了上瘾症。来源：Rockefeller大学分子生物实验室。

How does this affect behavior?

这种机制是怎样影响到行为的？

Behaviorally, removing acetylcholine from the habenula caused the mice to become insensitive to the rewarding properties of nicotine, and they did not develop a tolerance to continued nicotine exposure. In addition, these mice did not experience withdrawal symptoms, such as body shakes and scratching. These findings and others indicate that without acetylcholine, nicotine addiction would not occur.

从行为上来说，去除了缰核中乙酰胆碱后的，这些老鼠对尼古丁奖励机制不再敏感，对加大尼古丁的吸收也不感兴趣。并且这些老鼠也没有出现例如浑身哆嗦、不断抓挠之类的戒断症状。这些研究结果揭示了一旦消除乙酰胆碱，尼古丁上瘾就不复存在。

Although smoking rates have decreased in recent years, there’s a consistent portion of the population that continues to smoke, and a continued need for research into tobacco addiction. This study helps us understand a bit more about the brain circuitry involved in this dependence, which is also relevant to opioid and cannabinoid addiction.

尽管近些年来吸烟率有所下降，但是仍然有很多顽固的烟民，因此我们必须坚持对烟草上瘾的研究。这种研究能够帮助我们增加一点对脑神经系统的理解，这包括对药物依赖的理解，还包括对鸦片类和大麻类毒品上瘾症的理解。

Next, the Ibanez-Tallon group is interested in understanding how the interaction between acetylcholine and glutamate may work in other areas of the brain. “Because most nerve cells that release acetylcholine also release glutamate at the same time, the next challenge is to investigate whether the synergy between these two neurotransmitters is important for other functions that involve acetylcholine, such as memory and cognition.”

Ibanez-Tallon研究组的下一步计划是研究脑部其他区域中乙酰胆碱和谷氨酸是如何相互作用的。“因为大部分释放乙酰胆碱的神经同时也会释放谷氨酸，所以我们的下一个挑战是研究这两种重要的神经递质的协同增效机制是否会对其他脑功能产生影响，例如记忆和认知。”