Cocaine self-administration produces a persistent increase in dopamine D2High receptors
Cocaine self-administration produces a persistent increase in dopamine D2High receptors
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DOI：
10.1016/j.euroneuro.2008.01.002
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发表时间：
2008-08-01
影响因子：
5.6
通讯作者：
Robinson, Terry E.
中科院分区：
文献类型：
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作者：
Briand, Lisa A.;Flagel, Shelly B.;Robinson, Terry E.
据报道，可卡因成瘾者的纹状体多巴胺D2受体数量减少。然而，在啮齿类动物中，重复的可卡因给药始终产生对间接多巴胺激动剂（如可卡因本身）的精神兴奋激活作用的超敏反应，重要的是，对直接作用的D2受体激动剂的超敏反应。目前的研究报告可能解决这个长期存在的悖论。多巴胺D2受体以低亲和力和高亲和力状态存在，多巴胺通过功能上更相关的高亲和力D2受体（D2（高））发挥其作用。我们在这里报告说，可卡因自我给药经历使纹状体中D2（高）受体的比例大幅增加（约150%），而D2受体总数没有变化，并且这种效果在3天和30天后都很明显。可卡因自我给药停止。在人（和非人灵长类动物）成像研究中使用的探针，D2（高）受体的变化不明显。因此，我们认为，可卡因成瘾者和以前用可卡因治疗的动物可能对多巴胺能药物反应过度，部分原因是D2（高）受体的增加导致多巴胺超敏。这也可能有助于解释为什么增加多巴胺神经传递的刺激，包括药物本身，在有可卡因暴露史的个体中产生复发是如此有效。(C)2008 Elsevier B.V.和ECNP。All rights reserved.
Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high-affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2(High)). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2(High) receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2(High) receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2(High) receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine. (C) 2008 Elsevier B.V. and ECNP. All rights reserved.