11月30日，国际权威学术期刊《神经科学杂志》上刊登了复旦大学医学神经生物学国家重点实验室主任郑平教授带领研究生经过3年多的研究成果（Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala），该研究团队发现戒断成瘾药物后所产生的痛苦与激活脑内另一个脑区杏仁核多巴胺系统有关，提示如果对杏仁核多巴胺系统进行干预，对减少“药物成瘾者”因环境因素导致的“药物复吸”顽症有重要意义。
这一研究得到了科技部“973”计划、国家自然科学基金委创新群体项目等方面的支持资助。据郑平介绍，药物成瘾是全球普遍存在的公共卫生问题，也是危害严重的社会问题。实践证明，药物成瘾者即使“戒毒”后，也会不顾一切地去寻求药物，一是为了享受成瘾药物所带来的“快感”，二是为了消除戒毒后难以忍受的“痛苦”。研究证明，成瘾药物产生的快感和痛苦与环境中的各种线索相互作用后，会使药物成瘾者产生“关联性记忆”，使他们一遇到“相关线索”便会激活“相关记忆”，产生觅药、用药的冲动，从而导致复吸行为发生。但药物成瘾者的快感和痛苦症状是通过何种“神经机制”与环境中的线索相“偶联”的，一直是科学家有待解决的难题。
为了寻觅解开这一难题的钥匙，郑平指导他的研究生将吗啡成瘾鼠放在两个环境不同的盒子中，然后在一个盒子中使成瘾鼠突然戒断吗啡，这时成瘾鼠会产生“痛苦”的戒断症状，并且将这一痛苦与其所处这个盒子的特殊环境“有机地”联系在一起；以后将这个鼠再放到这一环境中，它就会“回想”起当初药物戒断时的痛苦，从而迅速“逃离”这一环境。但是，如果用药物干预的方法，将成瘾鼠杏仁核内的多巴胺Ｄ１受体进行抑制后，再将大鼠放入同样盒子中，它会“忘记”先前所受的痛苦，且并不“逃离”这个环境。
研究人员针对上述现象，深入研究了吗啡成瘾鼠脑内杏仁核的变化，发现吗啡使多巴胺对脑内“活性分子”谷氨酸的作用由原来的抑制逆转为兴奋，而这种兴奋是因为吗啡“动员”了杏仁核突触前部位原本“沉默”的多巴胺Ｄ１受体，使其介导的信号传导通路功能由“低迷”转为“亢进”，从而逆转了杏仁核内多巴胺对谷氨酸的作用。结果证明，吗啡成瘾鼠脑内杏仁核中多巴胺对谷氨酸作用的逆转，可能是将药物戒断后的“痛苦”症状与周围环境线索“偶联”的重要神经机制，如果对这一成瘾机制进行干预，可能成为减少药物成瘾者因环境因素导致药物复吸的新策略。(生物谷Bioon.com)
doi:10.1523/JNEUROSCI.3806-11.2011
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Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala
Zicheng Li1,2,*, Wenjie Luan1,*, Yang Chen1,*, Ming Chen1, Yi Dong1, Bin Lai1, Lan Ma1, and Ping Zheng1
Dopaminergic signaling in the basolateral amygdala (BLA) is important for drug-stimulus learning that triggers relapse to drug-seeking behavior. However, little is known about adaptive changes in this signaling pathway upon chronic morphine treatment. In this paper, we observed the influence of chronic morphine treatment on the effect of dopamine (DA) on the excitatory transmission in the pyramidal cells of BLA in slices with the whole-cell patch-clamp method. We also studied its mechanism and significance with pharmacological approaches combined with biochemical and behavioral techniques. The results showed that chronic morphine exposure switched the effect of DA on the excitatory synaptic transmission from inhibition to excitation; the chronic morphine-induced switching action on the effect of DA was due to its influence on D1 receptors; the site of the effect of chronic morphine treatment on D1 receptors was at presynaptic locus; chronic morphine treatment induced a significant increase in the amount of D1 receptor expression in the synaptosomes and synaptosomal membrane fraction from BLA; the enhancement of presynaptic glutamate release by D1 receptor agonist upon chronic morphine treatment was dependent on the activation of cAMP-dependent protein kinase; and the intra-BLA injection of D1 receptor antagonist canceled the conditioned place aversion (CPA) in morphine-dependent rats. In conclusion, chronic morphine treatment switches the effect of DA on the excitatory synaptic transmission from inhibition to excitation by the presynaptic D1 receptor amount increase-mediated glutamate release in the pyramidal cells of BLA and the blockade of D1 receptors in BLA cancels CPA in morphine-dependent rats.
