Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users
Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users
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DOI：
10.1038/npp.2016.108
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发表时间：
2016-12-01
影响因子：
7.6
通讯作者：
Kish, Stephen J.
中科院分区：
文献类型：
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作者：
Boileau, Isabelle;Payer, Doris;Kish, Stephen J.
在兴奋剂使用（如可卡因，甲基苯丙胺）障碍的神经影像学研究表明，多巴胺升高药物减少多巴胺释放是复发的一个潜在标志，并建议增加D-2/3受体的多巴胺可能是有益的治疗。相反，最近的研究表明，兴奋剂使用者的D-3受体水平升高，促使人们认为D-3拮抗作用可能有助于防止复发。在这里，我们测试了甲基苯丙胺（MA）用户对苯丙胺的“迟钝”反应是否延伸到富含D-3的大脑区域。14名MA使用者和15名健康对照者在基线和苯丙胺（0.4 mg/kg）后使用D-3偏好探针[C-11]（+）-PHNO完成了两次正电子发射断层扫描。相对于健康对照组，MA使用者在富含D-3的黑质（36 vs 20%，p= 0.03）和苍白球（30 vs 17%，p = 0.06）中使用安非他明后[C-11]（+）- PHNO结合（增加多巴胺释放）的降低更大，这与自我报告的“药物需求”相关。在富含D-2的纹状体中，我们没有观察到对安非他明的“钝化”多巴胺反应;然而，药物使用的严重程度与安非他明诱导的[C-11]-（+）-PHNO结合的纹状体变化呈负相关。我们的研究提供的证据表明，多巴胺在纹状体外'D-3区'的传输是不是钝化，而是增加MA用户。结合我们之前发现的MA使用者中D-3受体水平升高，目前的观察结果表明，D-3多巴胺受体的多巴胺能传递可能有助于使用药物的动机，并支持D-3拮抗作用作为一种可能的治疗工具，以减少MA成瘾的渴望和复发。
Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamineelevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D-2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D-3 receptor levels in stimulant users prompting the view that D-3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D-3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D-3-preferring probe [C-11](+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [C-11](+)- PHNO binding (increased dopamine release) after amphetamine in D-3-rich substantia nigra (36 vs 20%, p= 0.03) and globus pallidus (30 vs 17%, p = 0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D-2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [C-11]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D-3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D-3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D-3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D-3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.