利用正电子放射X射线断层摄影术（positron emission tomography ，PET），由Wake Forest大学医学研究院Michael A. Nader博士带领的研究小组证实一种特异的脑化学特征和可卡因滥用程度有关，为治疗毒品沉溺提供了新的曙光。
动物（猕猴，猕猴是公认的用于研究人类毒品使用情况的极好模型，生物谷注）实验显示：可卡因使用前和开始沉溺于可卡因以后，大脑局部神经传递素多巴胺受体数量与药品剂量有显著相关性，可卡因的使用量越大多巴胺受体数量越少。
先前的研究证实不论在人体或者是动物，可卡因滥用者和不用者相比，体内一种叫做D2的多巴胺受体表达量偏低，但是D2表达量偏低和可卡因滥用的因果关系不能确定。
Nader和其同事在《自然神经科学》杂志网络版文章中写到：“猴子实验显示两个条件互为因果关系。D2表达水平偏低的个体更容易继续服用可卡因，因为可卡因降低了D2受体的水平。”
实验首次对没有使用过可卡因动物的D2基线水平与开始服用后D2水平的变化进行对比，但是这种对比不适用于人类。早期的猴子实验，实验组也只是和没有服用过可卡因的空白对照组相比，而不是其本身的服用前后变化比值。研究显示，开始使用可卡因引起D2水平显著下降，继续使用会使D2水平表达在基线以下。
“总之，这些结果明确说明多巴胺D2受体在可卡因滥用中的角色，提示给动物注射逐渐增多的D2受体可能会减轻服用毒品的痛苦。”提示可以通过药理学或者改善环境因素，如降低压力的方法，提高D2受体水平。但是“目前为止，临床上还没有有效地治疗可卡因上瘾的疗法，并且，可卡因易上瘾人群的生理学诱导机制和环境诱导机制仍没有被研究清楚。”
同其它神经传递素一样，多巴胺在脑神经细胞间运动、传递“信号”。“一个神经细胞释放多巴胺分子，然后另一个神经细胞通过细胞表面的受体（比如D2）纳入被释放的多巴胺。剩下的多巴胺分子通过“传输机”回收后被送回原来的细胞。
可卡因进入“传输机”，多巴胺的再回收受到阻止，但是这些“传输机”仍吸收环境中的D2受体。药物研究人员猜想是因为这种变化造成了对毒品的依赖：受体水平下降后患者需要更多的多巴胺去弥补“正常”感觉。
像服用可卡因一样，压力也可以提高多巴胺的水平，明显地引起D2受体浓度上升。Nader小组早期的研究发现压力和滥用可卡因倾向有关。
但是在对猴子一年的研究中，D2受体水平平均下降了21％，其中三只猴子在结束实验三个月内得到恢复，另外两只没有恢复到D2的基线水平，并证明没有得到恢复与开始时D2的基线水平无关。研究显示“其他因素，比如其他神经传递素系统，可能参与D2受体功能的恢复。”
英文原文：
Cocaine Abuse And Receptor Levels: PET Imaging Confirms Link
Using positron emission tomography (PET), researchers have established a firm connection between a particular brain chemistry trait and the tendency of an individual to abuse cocaine and possibly become addicted, suggesting potential treatment options.
The research, in animals, shows a significant correlation between the number of receptors in part of the brain for the neurotransmitter dopamine - measured before cocaine use begins - and the rate at which the animal will later self-administer the drug. The research was conducted in rhesus monkeys, which are considered an excellent model of human drug users.
Generally the lower the initial number of dopamine receptors, the higher the rate of cocaine use, the researchers found. The research was led by Michael A. Nader, Ph.D., professor of physiology and pharmacology at Wake Forest University School of Medicine.
It was already known that cocaine abusers had lower levels of a particular dopamine receptor known as D2, in both human and animal subjects, compared to non-users. But it was not known whether that was a pre-existing trait that predisposed individuals to cocaine abuse or was a result of cocaine use.
"The present findings in monkeys suggest that both factors are likely to be true," Nader and colleagues write in a study published online this week in the journal Nature Neuroscience. "The present findings also suggest that more vulnerable individuals are even more likely to continue using cocaine because of the cocaine-induced reductions in D2 receptor levels."
This was the first study ever to measure the baseline D2 levels of animals that had never used cocaine and compare those levels to changes in D2 receptors after the animals had started using. This kind of comparison is not possible with human subjects, and in previous monkey research, the brain chemistry of animals exposed to cocaine was compared only with non-using "controls."
The research also showed that starting to use cocaine caused the D2 levels to drop significantly and that continuing to use the drug kept the D2 levels well below the baseline.
"Overall, these findings provide unequivocal evidence for a role of [dopamine] D2 receptors in cocaine abuse and suggest that treatments aimed at increasing levels of D2 receptors may have promise for alleviating drug addition," the researchers write.
The study suggested that increasing D2 receptors might be done "pharmacologically" or by improving environmental factors, such as reducing stress. But, the study notes, "at present there are no clinically effective therapies for cocaine addiction, and an understanding of the biological and environmental mediators of vulnerability to cocaine abuse remains elusive."
Dopamine, like other neurotransmitters, moves between nerve cells in the brain to convey certain "messages." It is released by one nerve cell and taken in by the receptors on the next nerve cell, some of which are D2. Unused dopamine is collected in "transporters" that return it to the sending cell.
Cocaine operates by entering the transporter, blocking the "reuptake" of dopamine and leaving more of it in the space between the cells. It is thought that this overload of dopamine gives the user the cocaine "high."
But this dopamine overload also overwhelms the D2 receptors on the receiving cells, and those cells eventually react by reducing the number of D2 receptors. Drug researchers hypothesize that it is this change that creates a craving for cocaine: once the receptor level drops, more dopamine is needed for the user even to feel "normal."
Like cocaine use, stress can also increase the dopamine levels and apparently cause a reduction in the D2 receptors. Earlier research by Nader's team at Wake Forest showed a connection between stress and a tendency to abuse cocaine.
The current study also observed differences in the time it took for the D2 receptors to return to normal levels once cocaine use ended. Monkeys that used only for one week had only a 15 percent reduction in D2 receptors and recovered completely within three weeks.
But monkeys that used for a year averaged a 21 percent reduction in D2 receptors. Three of those monkeys recovered within three months, but two of those monkeys still had not returned to their baseline D2 levels after one year of abstinence.
Lack of recovery was not related to initial baseline D2 levels. The study suggests that "other factors, perhaps involving other neurotransmitter systems, mediate the recovery of D2 receptor function."
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Other researchers involved in the study were H. Donald Gage, Ph.D., Susan H. Nader, B.S., Tonya L. Calhoun, M.S., Nancy Buchheimer, B.S., and Richard Ehrenkaufer, Ph.D., all of Wake Forest, Drake Morgan, Ph.D., now at the University of Florida College of Medicine, and Robert H. Mach, Ph.D., now at Washington University School of Medicine. The full study article is available at http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn1737.html.
Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 32nd in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.
