利用正電子放射X射線斷層攝影術（positron emission tomography ,，PET），由Wake Forest大學醫(yī)學研究院Michael A. Nader博士帶領的研究小組證實一種特異的腦化學特征和可卡因濫用程度有關,，為治療毒品沉溺提供了新的曙光。
動物（獼猴,，獼猴是公認的用于研究人類毒品使用情況的極好模型,，生物谷注）實驗顯示：可卡因使用前和開始沉溺于可卡因以后，大腦局部神經(jīng)傳遞素多巴胺受體數(shù)量與藥品劑量有顯著相關性,，可卡因的使用量越大多巴胺受體數(shù)量越少,。
先前的研究證實不論在人體或者是動物，可卡因濫用者和不用者相比,，體內(nèi)一種叫做D2的多巴胺受體表達量偏低,，但是D2表達量偏低和可卡因濫用的因果關系不能確定。
Nader和其同事在《自然神經(jīng)科學》雜志網(wǎng)絡版文章中寫到：“猴子實驗顯示兩個條件互為因果關系,。D2表達水平偏低的個體更容易繼續(xù)服用可卡因,，因為可卡因降低了D2受體的水平。”
實驗首次對沒有使用過可卡因動物的D2基線水平與開始服用后D2水平的變化進行對比,，但是這種對比不適用于人類,。早期的猴子實驗，實驗組也只是和沒有服用過可卡因的空白對照組相比,，而不是其本身的服用前后變化比值,。研究顯示，開始使用可卡因引起D2水平顯著下降,，繼續(xù)使用會使D2水平表達在基線以下,。
“總之，這些結(jié)果明確說明多巴胺D2受體在可卡因濫用中的角色,，提示給動物注射逐漸增多的D2受體可能會減輕服用毒品的痛苦,。”提示可以通過藥理學或者改善環(huán)境因素，如降低壓力的方法,，提高D2受體水平,。但是“目前為止，臨床上還沒有有效地治療可卡因上癮的療法,，并且,，可卡因易上癮人群的生理學誘導機制和環(huán)境誘導機制仍沒有被研究清楚。”
同其它神經(jīng)傳遞素一樣,，多巴胺在腦神經(jīng)細胞間運動,、傳遞“信號”。“一個神經(jīng)細胞釋放多巴胺分子，然后另一個神經(jīng)細胞通過細胞表面的受體（比如D2）納入被釋放的多巴胺,。剩下的多巴胺分子通過“傳輸機”回收后被送回原來的細胞,。
可卡因進入“傳輸機”，多巴胺的再回收受到阻止,，但是這些“傳輸機”仍吸收環(huán)境中的D2受體,。藥物研究人員猜想是因為這種變化造成了對毒品的依賴：受體水平下降后患者需要更多的多巴胺去彌補“正常”感覺。
像服用可卡因一樣,，壓力也可以提高多巴胺的水平,，明顯地引起D2受體濃度上升。Nader小組早期的研究發(fā)現(xiàn)壓力和濫用可卡因傾向有關,。
但是在對猴子一年的研究中,，D2受體水平平均下降了21％，其中三只猴子在結(jié)束實驗三個月內(nèi)得到恢復,，另外兩只沒有恢復到D2的基線水平,，并證明沒有得到恢復與開始時D2的基線水平無關。研究顯示“其他因素,，比如其他神經(jīng)傳遞素系統(tǒng),，可能參與D2受體功能的恢復。”
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.
