Neuroimaging and physiological evidence for involvement of glutamatergic transmission in regulation of the striatal dopaminergic system.
Neuroimaging and physiological evidence for involvement of glutamatergic transmission in regulation of the striatal dopaminergic system.
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神经影像学和生理证据表明谷氨酸能传播参与纹状体多巴胺能系统的调节。
DOI：
10.1523/jneurosci.2559-08.2009
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发表时间：
2009-02-11
期刊：
影响因子：
--
通讯作者：
Suhara T
中科院分区：
文献类型：
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作者：
Tokunaga M;Seneca N;Shin RM;Maeda J;Obayashi S;Okauchi T;Nagai Y;Zhang MR;Nakao R;Ito H;Innis RB;Halldin C;Suzuki K;Higuchi M;Suhara T
通过谷氨酸和多巴胺受体的异常神经传递一直是精神疾病分子基础生物医学研究的焦点，但它们相互作用的模式尚未被发现。在这项研究中，我们证明了药理学逆转甲基苯丙胺刺激的多巴胺能溢出抑制组I代谢型谷氨酸（mGlu）受体在活的灵长类动物和啮齿类动物。使用多巴胺D2/3受体的完全激动剂示踪剂（R）-2- 11 CH 3 O-N-正丙基去甲阿朴吗啡（[11 C]MNPA）对食蟹猴和大鼠进行体内正电子发射断层扫描（PET），并通过扫描清醒受试者来避免由于麻醉引起的动力学数据波动。甲基苯丙胺诱导的多巴胺过度释放和通过用I组mGlu受体拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）治疗消除这种改变，在两个物种中分别测量为由于多巴胺增加而降低的结合电位及其恢复至基线水平。MPEP对甲基苯丙胺诱导的多巴胺溢出的抵消作用也得到了未麻醉大鼠纹状体微透析的神经化学支持。此外，膜片钳电生理分析，使用急性脑切片制备大鼠表明，直接目标的MPEP机制参与甲基苯丙胺的影响是本地纹状体内。根据我们的PET和电生理数据，由于单独的MPEP没有显著改变基线多巴胺能神经传递，因此本研究结果共同扩展了对多巴胺-谷氨酸串扰的认识，从负责mGlu受体的纹状体外定位到纹状体内协同作用，并支持在纹状体多巴胺能状态紊乱的情况下使用可通过体内成像技术评估的I组mGlu受体拮抗剂进行治疗干预。
Aberrant neurotransmissions via glutamate and dopamine receptors have been the focus of biomedical research on the molecular basis of psychiatric disorders, but the mode of their interaction is yet to be uncovered. In this study, we demonstrated the pharmacological reversal of methamphetamine-stimulated dopaminergic overflow by suppression of group I metabotropic glutamate (mGlu) receptor in living primates and rodents. In vivo positron emission tomography (PET) was conducted on cynomolgus monkeys and rats using a full agonistic tracer for dopamine D2/3 receptor, (R)-2-11CH3O-N-n-propylnorapomorphine ([11C]MNPA), and fluctuation of kinetic data due to anesthesia was avoided by scanning awake subjects. Excessive release of dopamine induced by methamphetamine and abolishment of this alteration by treatment with an antagonist of group I mGlu receptors, 2-methyl-6-(phenylethynyl)pyridine (MPEP), were measured in both species as decreased binding potential due to increased dopamine and its recovery to baseline levels, respectively. Counteraction of MPEP to the methamphetamine-induced dopamine spillover was also supported neurochemically by microdialysis of unanesthetized rat striatum. Moreover, patch-clamp electrophysiological assays using acute brain slices prepared from rats indicated that direct targets of MPEP mechanistically involved in the effects of methamphetamine are present locally within the striatum. As MPEP alone did not markedly alter the baseline dopaminergic neurotransmission according to our PET and electrophysiological data, the present findings collectively extend the insights on dopamine-glutamate crosstalk from extrastriatal localization of responsible mGlu receptors to intrastriatal synergy, and support therapeutic interventions in case of disordered striatal dopaminergic status using group I mGlu receptor antagonists assessable by in vivo imaging techniques.