首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia.
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Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia.

机译:mGluR5 ADX47273的正变构调节剂对精神分裂症模型大鼠的条件回避反应和PCP诱导的运动过度的影响。

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摘要

Metabotropic glutamate receptors of the subtype 5 (mGluR(5)) are located in brain regions implicated in schizophrenia such as the cerebral cortex or the nucleus accumbens. They may therefore provide an interesting target for the treatment of psychoses. Currently available agonists of mGluR(5) are not selective, do not penetrate the brain and induce a tonic activation resulting in a rapid desensitization. Therefore, the research focus was shifted to positive allosteric modulators (PAMs). Subsequently several mGluR(5) PAMs have been discovered, e.g. ADX47273 (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-y l}-methanone). In the present study, effects of ADX47273 (1-100mg/kg) were evaluated in rat models used for detecting antipsychotic-like activity: the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion models. Furthermore, the cataleptogenic potential of ADX47273 was compared to that of haloperidol. ADX47273 (100mg/kg) and various clinically used neuroleptics (haloperidol, olanzapine, and aripiprazole) attenuated CAR behaviour in rats. However, ADX47273 and aripiprazole failed to reduce the PCP-induced hyperlocomotion, whereas olanzapine and haloperidol diminished it. In contrast to haloperidol, ADX47273 (100mg/kg) failed to induce consistent catalepsy in rats. In conclusion, ADX47273 shows promising antipsychotic activity in some tests which require future investigation.
机译:亚型5(mGluR(5))的代谢型谷氨酸受体位于与精神分裂症有关的大脑区域,例如大脑皮层或伏隔核。因此,它们可以提供治疗精神病的有趣靶标。当前可用的mGluR(5)激动剂不是选择性的,不能穿透大脑并诱导滋补剂激活,从而导致快速脱敏。因此,研究重点转移到了正构构调节剂(PAM)。随后发现了几个mGluR(5)PAM,例如ADX47273(S-(4-氟-苯基)-{3- [3-(4-氟-苯基)-[1,2,4]恶二唑-5-基]-哌啶-1-基l}-甲酮)。在本研究中,在用于检测抗精神病样活性的大鼠模型中评估了ADX47273(1-100mg / kg)的作用:条件回避反应(CAR)和苯环利定(PCP)诱导的运动过度模型。此外,比较了ADX47273和氟哌啶醇的致晕作用。 ADX47273(100mg / kg)和各种临床使用的抗精神病药(氟哌啶醇,奥氮平和阿立哌唑)可减轻大鼠的CAR行为。但是,ADX47273和阿立哌唑未能降低PCP引起的运动过度,而奥氮平和氟哌啶醇却能减少这种运动。与氟哌啶醇相反,ADX47273(100mg / kg)未能在大鼠中引起持续的僵直。总之,ADX47273在某些需要进一步研究的测试中显示出令人鼓舞的抗精神病活性。

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