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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease.
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Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease.

机译：在帕金森氏病的啮齿动物模型中，靶向III型代谢型谷氨酸受体会产生复杂的行为效应。

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Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/microl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABA(A) receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.
机译：激活III类代谢型谷氨酸受体（mGluRs）的药物代表了L-DOPA（L-3,4-二羟基苯丙氨酸）的替代疗法，用于治疗帕金森氏病（PD）。它们在基底神经节核内的GABA能和谷氨酸能突触中的突触前位置提供了减少与PD相关的异常活动的关键靶标。选择性III型mGluR激动剂（1S，3R，4S）-1-氨基环戊烷-1,3,4-三羧酸（ACPT-1）和L-（+）-2-氨基-4-膦酰基丁酸（L因此，在PD大鼠模型中研究了输注至苍白球（GP）或黑质网状组织（SNr）的-AP4）。将ACPT-1（1、2.5和5 nmol / microl）双向输注到GP中可完全逆转6-羟基多巴胺黑质纹状体多巴胺损伤在反应时间任务中产生的严重运动缺乏，而不会影响对照的表现。将L-AP4（1 nmol）或微毒素（一种GABA（A）受体拮抗剂）注入GP后，观察到相似的结果。此外，苍白球内ACPT-1可抵消氟哌啶醇引起的僵直。通过同时施用选择性III组受体拮抗剂（RS）-α-环丙基-4-膦酰基苯基甘氨酸，可以逆转这种作用。相反，向SNr中输注ACPT-1（0.05、0.1和0.25 nmol）可以增强对照组和患病大鼠的病变诱导的运动能力缺乏，并且不能逆转氟哌啶醇引起的僵直。 SNr中的L-AP4（0.05 nmol）和微毒素产生相同的效果。总之，这些结果表明，GP中III组mGluRs的激活可能通过调节GABA能神经传递而在帕金森病大鼠中提供了益处。用选择性mGluR8激动剂也观察到了SNr中III组mGluR激活所产生的相反作用，支持使用亚型选择性III组mGluR激动剂作为潜在的帕金森病治疗策略。

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