Sergeeva O A, Doreulee N, Chepkova A N, Kazmierczak T, Haas H L
Department of Neurophysiology, Heinrich-Heine-University, D-40001, Dusseldorf, Germany.
Eur J Neurosci. 2007 Oct;26(7):1889-94. doi: 10.1111/j.1460-9568.2007.05815.x. Epub 2007 Sep 14.
In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.
在早期帕金森病（PD）模型中，运动功能障碍伴随着纹状体谷氨酸受体的过度激活。I 型代谢型谷氨酸受体（mGluR I）在 PD 进展中起重要作用，但尚未完全明确。在小鼠脑片中，浴加 mGluR I 激动剂（RS）-DHPG（3,5-二羟基苯甘氨酸，100 微摩尔，作用 20 分钟）可导致皮质纹状体传递的长期抑制（LTD(DHPG)），三种 mGluR I 拮抗剂：LY 367385、CPCCOEt 和 MPEP 可逆转这种抑制。LTD(DHPG)需要一氧化氮（NO）合成，因为它被广谱 NO 合酶（NOS）抑制剂 Nω-硝基-L-精氨酸（NL-Arg）阻断，并且在神经元 NOS 阻断和内皮 NOS 缺陷小鼠中受到损害。内源性大麻素（eCB）的释放关键参与了这种形式的纹状体可塑性，因为 CB1 受体拮抗剂 AM251 可预防 LTD(DHPG)，而 CB1 激动剂 ACEA 可引发 LTD。LTD(DHPG)诱导所需的 NO 合成发生在 CB1 激活的下游，因为 NL-Arg 也可消除 ACEA 诱发的 LTD。这些发现与 PD 的病理生理学相关，因为它们将 I 型 mGluRs 的过度激活与纹状体 NO 产生联系起来。
