Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine
Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine
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DOI：
10.1007/s002130050072
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发表时间：
2000-03-01
影响因子：
3.4
通讯作者：
Schoepp, DD
中科院分区：
文献类型：
--
作者：
Cartmell, J;Monn, JA;Schoepp, DD
原理：最近的研究使用苯环利定（PCP）作为精神病模型，涉及精神分裂症的代谢型谷氨酸（mGlu）受体。我们已经表明，使用自动运动活动监测系统，选择性II组mGlu受体激动剂减弱PCP（5 mg/kg）诱发的走动和精细运动增加，与非典型抗精神病药氯氮平的特征相似。目的和方法：由于自动化系统不能区分特定的PCP诱发行为，因此在本文中，我们通过观察方法评估了强效mGlu 2/3受体激动剂LY 379268对PCP诱发行为的影响。此外，我们还比较了LY 379268与非典型抗精神病药氯氮平的作用。结果：LY 379268和氯氮平均能抑制PCP诱导的大鼠跌倒、翻身和后蹬反应，且呈剂量依赖性。PCP给药后30分钟，1 mg/kg LY 379269分别使福尔斯和转身减少89%和53%，1 mg/kg氯氮平使转身减少70%。有趣的是，低剂量的氯氮平增加了PCP引起的福尔斯跌倒。反向踩踏对LY 379268和氯氮平特别敏感，PCP给药后30分钟，1 mg/kg的任何一种药物均可完全消除反向踩踏。然而，与LY 379268相反，氯氮平对这些行为的减弱仅发生在增强PCP诱发的共济失调的剂量下。此外，LY 379268不影响PCP诱发的前爪踩踏。结论：这些结果表明，mGlu 2/3受体不介导运动活动的普遍减少，而是选择性地调节特定的PCP行为，进一步暗示II组mGlu受体作为治疗精神分裂症的可行药物靶点。
Rationale: Recent studies using phencyclidine (PCP) as a model for psychosis have implicated metabotropic glutamate (mGlu) receptors in schizophrenia. We have shown, using an automated motor activity monitoring system, that selective group II mGlu receptor agonists attenuate PCP (5 mg/kg)-evoked increases in ambulations and fine motor movements with similar profiles to the atypical antipsychotic, clozapine. Objective and methods: Because the automated system does not dis criminate between specific PCP-evoked behaviors, in this paper we examined the effects of the potent mGlu2/3 receptor agonist LY379268 on PCP-evoked behaviors as assessed by observational methods. Furthermore, we have compared the actions of LY379268 to the atypical antipsychotic clozapine. Results: LY379268 and clozapine reduced the expression of PCP-induced falling, turning and back pedaling in a dose-dependent manner. Thirty minutes post-PCP administration, 1 mg/kg LY379269 reduced falls and turns by 89% and 53%, respectively, and 1 mg/kg clozapine attenuated turning by 70%. Interestingly, low doses of clozapine increased PCP-elicited falls. Back-pedaling was particularly sensitive to LY379268 and clozapine, with 1 mg/kg of either agent completely abolishing back-pedaling 30 min after PCP administration. However, in contrast to LY379268, attenuation of these behaviors by clozapine only occurred at doses that augmented PCP-evoked ataxia. Furthermore, LY379268 did not affect PCP-evoked forepaw treading. Conclusions: These results indicate that mGlu2/3 receptors do not mediate a generalized reduction in motor activity, but instead selectively modulate specific PCP behaviors, further implicating group II mGlu receptors as viable drug targets in the treatment of schizophrenia.