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“酒”字的演变
饮酒文化是任何文化都不可或缺的一部分，我泱泱华夏文明更甚。凡是才子都与酒有不解之缘。
风流才子如李白：天子呼来不上船，自称臣是酒中仙。
唐寅：但愿长醉花酒间，不愿鞠躬车马前。
还有“太守醉也”的欧阳修，“把酒问青天”的苏东坡，更毋庸提“酒仙”刘伶，“酒鬼”李贺，“酒圣”杜甫。酒俗文化源远流长，甲骨文中就有迹可循。人类自从有了发酵技术就沉迷于酒精，这其中固然有社会文化因素，喜要喝酒（烹羊宰牛且为乐 会须一饮三百杯）、悲也要喝酒（抽刀断水水更流 举杯销愁愁更愁），但也许没有想到的是，饮酒成性还有生物学因素。看来酒也不是你想喝想喝就能喝，不想喝不想喝就能挥手bye bye，大步走开。
Addicted or Afflicted? 酒仙和酒鬼之间，差着一个GABA
爱饮酒者多，但酗酒者（即被酒精捆绑，无法自由选择其它消遣模式者）大概稳定地占喝酒人数的15%。为了模拟酗酒，瑞典的一队科学家用620只大鼠做实验。大鼠和人一样，偏爱甜食、爱喝糖水。学者们先用十周左右的时间让大鼠自行熟悉和饮用20%的酒精，然后同时将糖水和酒精放在大鼠笼子里。大部分大鼠在有了糖水的选择后，都不再饮用酒精，只有极少的一部分（95/620）持续饮用酒精。对于这95只“上瘾”的大鼠，科学家们发现，即使在酒精里掺入大鼠们不喜的一种苦涩的物质醌、或者在他们每次喝酒时电击脚掌，仍然无法阻挡“上瘾”大鼠一颗勇往直前的心。
觥筹影中死，做鬼也风流。
难喝不能阻挡我、疼痛不能阻挡我、妻离子散家破人亡不能阻挡我。你便是落了我牙、歪了我嘴、瘸了我腿、折了我手，天赐与我这几般儿歹症候，尚兀自不肯休。则除是阎王亲自唤，神鬼自来勾，三魂归地府，七魄丧冥幽，天那，那其间方能罢酒！（1）
Addicted or Afflicted? 酒仙和酒鬼之间，差着一个GABA
这些大鼠到底怎么了？它们的大脑与喝糖水的大鼠有什么不一样？
科学家们把爱喝酒和不爱喝酒的大鼠大脑不同部位的基因表达进行了对比，发现很多明显的区别位于大脑杏仁核！杏仁核是大脑中负责产生、识别和调整情绪、以及控制学习和记忆的部位。而这其中表达量变化最大的就是GABA传导通路中的GABA受体。
大脑区域简图
GABA即r-氨基丁酸，是神经传导中一个重要的因子，缺乏GABA会使人失眠、恐慌、易怒。日常食用的普洱茶、泡菜，都是GABA的重要来源。在神经传导的过程中，神经元在刺激下把GABA释放到细胞间。传导结束后，细胞间的GABA则需要被迅速清除。而细胞间并不存在可以分解GABA的酶，它们只能通过GABA通道被重新运送回神经细胞内。可想而知，GABA受体和通道的减少会影响GABA迅速有效的消除。
研究者们发现，在酗酒的大鼠中，负责转运GABA的GAT-3转运体大量减少，造成GABA在细胞间的堆积。而奇妙的是，当人为的减少爱喝糖水的大鼠大脑中的GABA转运体时，它们也突然莫名的爱上了酒精！
GAT-3 的减少导致大鼠开始偏爱酒精（红色曲线）
这个实验的巧妙之处在于：成功的模拟了酗酒作为一种病的临床表现和概率，也似乎找到了原因 — GABA转运体的减少。原来人生的好多选择都是虚假的，看似自主选择，其实爱好与否、甚至上瘾与否，早就写在我们的基因里。
人类有时其实是傲慢的。在我们学会了用大脑思考抽象的、哲学的问题以后，我们开始鄙夷和摒弃自己的身体。殊不知一些我们自以为是自主的、自由的想法，实则仍然是在肉体的操控之下。这也不是第一个生物机能决定行为的例子了，一些病毒和寄生虫，不但可以影响身体健康，还能左右思维模式！最广为人知的例子大概就是弓形虫了。弓形虫的宿主是猫，只有在猫的体内才能繁殖，但可以短暂的寄居在人或者老鼠的身体中。猫捉老鼠、老鼠怕猫是亘古不变的真理。意料不到的是，当老鼠被弓形虫感染以后，神奇的事情发生了：老鼠不但不害怕猫，反而爱上了猫尿的味道！大无畏地把自己送入猫的口中，而目的只有一个：弓形虫需要重回猫的身体里进行繁殖。人类（非孕妇）感染弓形虫似乎没有特别明显的症状，实则是因为在现代社会，一个大活人被猫吃掉的概率也太小了。但是人类的远亲猩猩在感染了弓形虫以后，会莫名爱上豹子的体味，而豹子则是猩猩在自然界中少有的天敌。所以如果有一天突然爱上了铲屎官的工作，十有八九是病毒在思考。
图片来源：吾皇万睡工作室
我想这是一个很值得思考的哲学问题。我们的身体到底在多大程度上控制我们的行为？缺少GABA转运体相对来说更容易饮酒上瘾，但这也不是必然。环境因素（是否经常接触酒精）、性格因素（是否有极强的自控力）等都和生物学因素交杂在一起，成就了五彩斑斓的人生。或许真正的强大，是直面和克服自己的软弱，是明知不可为而为之。
不知不可为而为之，愚人也；知其不可为而不为，贤人也；知其不可为而为之，圣人也。（2）
最后，我想这也告诉我们，作为旁观者，看到“瘾君子”，或许我们应该更少论断他们的家庭、经历、自制力和人格，而更多的去体恤他们肉体上的软弱。
对酒当歌，人生几何？譬如朝露，去日苦多。
快意的人生需要酒精的点缀，而非绑架。
Addicted or afflicted?
When my husband and I first started dating, we took a leisurely stroll along a river in southwest China one summer evening. It was one of those lazy, perfect summer dusks, with children calling out and laughing as they swam like fishes in the river, and the hot, somewhat humid summer air settled like a warm but breathable shawl about one's shoulders. We stopped by a food cart that sold shaved ice and cold beer and I bought one of each. As we sat on a bench overlooking the river and the last traces of the sunset, I offered him the bottle of teeth-punchingly cold and soul-refreshing beer, to which he said, "sorry, I don't drink."
I believe that was the singular shakiest moment of our entire courtship.
One year into our marriage, I made for him a bottle opener for Valentine's Day. On it was written, "Happy Valentine's Day! - From 'The Reason You Drink' ". I believe that this is true on multiple levels, and that a heartfelt thank you is long overdue.
I love my drinks on weekends, my glass of wine, my gin and tonic, my occasional beer, and even the rarer shots of Chinese baijiu. Personally I feel it makes the rest and celebration of the weekends more wholesome. I am far from alone in my love of alcohol. It appears that in 2016, 5 billion liters of the beloved Chinese baijiu was sold alone. However, while the love of alcohol is widespread (it is the oldest recreational drug, after all), it appears that we may have less of a choice than we think when it comes to how much we love it. For some people (approximately 15% of the drinking population), the love of alcohol develops into a bigger problem: addiction.
A team of Swedish and American scientists tried to model human alcohol choice and addiction in lab rats. After training rats to self-administer 20% of alcohol for about 10 weeks, they were then given mutually exclusive choices between alcohol and sugar water. Like humans, rats have evolved to have a "sweet tooth", and when given the choice, most quickly chose sugar over alcohol. The experiment was repeated multiple times, and scientists found that 95 out of 620 (15.3%) rats consistently chose alcohol despite having a sugar alternative. These alcohol-preferring rats doggedly continued to choose alcohol even when faced with strong deterrents. They didn't care if the alcohol was adulterated with quinine (a bitter drug) to highly aversive concentrations. They ignored the pain from an electrical foot shock every time they drank. They pursued the drink with no fear of consequences. In other words, they were addicted.
So what's different about alcohol-preferring (AP) rats? Are their brains somehow wired differently? Scientists took sections from different regions of the AP rats' brains and compared gene expression patterns to the same brain regions of the non-addicted rats. Interestingly, a lot of the differences were clustered in the amygdala. The amygdala is an almond shaped part of the brain known to be associated with emotional responses such as anxiety, aggression and fear, as well as memory and learning. One of the genes most affected was a GABA transporter, GAT-3.
Decreased GAT-3 (left) resulted in accumulated GABA in extracellular space, leading to aberrant alcohol choice (3)
GABA -gamma-Aminobutyric acid - is an inhibitory neurotransmitter. It can reduce neuronal excitability, thereby decreasing stress and improving rest. When neurons fire, GABA is released into the extracellular space. It then needs to be cleared away from outside of the cells to create a sufficient GABA gradient in preparation for the next round of firing. However, no enzymes exist in the extracellular space to degrade GABA. Therefore, it must rely on transporters to relocate it back into the cell. Decrease of the GABA transporter GAT-3, as seen in the brains of AP rats, results in dysfunctional GABA clearance. Even more interestingly, when scientists manipulate the amount of GAT-3 inside the brains of non-addicted rats, these rats start showing a preference for alcohol over sugar! This suggests that low levels of GABA transporters might be the reason that AP rats became addicted in the first place.
Decreased GAT-3 resulted in preference for alcohol (red)
Our daily activities and choices are dictated by both our bodies and our minds. We'd like to think that for non-survival-essential choices such as the pursuit of pleasure, our minds play a bigger role than our bodies. Certainly, we'd like to believe that we are not mere creatures controlled by the whims of the physical. However, this is not the first example that we have fewer choices in life than we'd like to think. A well known mind twister is the parasite Toxoplasma gondii, which resides and breeds in cats but can infect both people and mice if they come into contact with cat feces. Mice make themselves scarce when they are in cat territory, but when they become infected by Toxoplasma gondii, they become fatally attracted to the smell of cats. Why? Because the parasite needs to make it back into its host in order to multiply and complete its life cycle. When humans get infected, the symptoms are harder to recognize, as the chances of any person being eaten by felines is infinitesimally small (now). However, when our primate cousins chimpanzees become infected, they become attracted to the smell of leopard urine, their only known predator in nature. So if you suddenly develop a love for scooping the litter, better think twice about whether your motivation comes from affection for your furry companion, or just a parasite twisting your mind!
The knowledge that some of our behavior is pre-written in our genes or in biology helps us in multiple ways. First of all it definitely lends us a tool to deal with unwelcome behavior. For example, in this case, elevating GAT-3 expression may alleviate alcohol addiction. Secondly, in this day and age, when we have progressed beyond judging people by their looks or socioeconomic status, but spare no mercy when it comes to judging people's life choices, perhaps it is important to recognize that some behaviors are rooted in pre-existing genetic and biological conditions. Of course, this cuts two ways. When we are the ones afflicted, knowing that we are biologically more susceptible may aid us in making wise decisions to err on the side of caution and exercise control when it comes to drinking. However, when those around us are affected, perhaps we should cut them some slack and admit that not all things can be controlled, despite our best intentions.
In Shakespeare's Othello, when the jealous Iago tries to persuade Cassio to drink while on duty, hoping to bring about his demotion, Cassio laments, "I have very poor and unhappy brains for drinking. I could well wish courtesy would invent some other custom of entertainment." I hope, for all our sakes, that when courtesy does invent it, we can all be free to choose it.
References
Eric Augier, Estelle Barbier, Russell S. Dulman, Valentina Licheri, Gaëlle Augier, Esi Domi, Riccardo Barchiesi, Sean Farris, Daniel Nätt, R. Dayne Mayfield, Louise Adermark, Markus Heilig. A molecular mechanism for choosing alcohol over an alternative reward. Science, 2018; 360 (6395): 1321 DOI: 10.1126/science.aao1157
(1) 关汉卿 《不伏老》
（2） 张岱 《四书遇》
(3) RAINER SPANAGEL Aberrant choice behavior in alcoholism. SCIENCE22 JUN 2018 : 1298-1299
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