Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and D-amphetamine models of schizophrenia.
Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and D-amphetamine models of schizophrenia.
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DOI：
10.1007/s00213-011-2200-0
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发表时间：
2011-07
影响因子：
3.4
通讯作者：
Neale, Joseph H.
中科院分区：
文献类型：
--
作者：
Profaci, Caterina P.;Krolikowski, Kristyn A.;Olszewski, Rafal T.;Neale, Joseph H.
关键词：
II组代谢型谷氨酸受体（mGluR）激动剂代表了治疗精神分裂症的新方法。由于肽神经递质N-乙酰基谷氨酸（NAAG）激活这些受体，NAAG肽酶抑制剂在概念上代表了一个平行的路径，朝着新的抗精神病药物的发展。虽然II组激动剂在精神分裂症的几种动物模型中是有效的，但据报道它们在调节苯环利定（PCP）对在这种疾病中发现的感觉处理缺陷的动物模型中的声惊吓的前脉冲抑制的作用方面缺乏功效。本研究的目的是重新检查第II组代谢型谷氨酸激动剂和NAAG肽酶抑制剂在两种小鼠品系的精神分裂症前脉冲抑制模型中的疗效。所使用的方法是一种测定，以确定这些药物在缓和用PCP和D-苯丙胺处理的小鼠的声惊吓的前脉冲抑制的减少中的功效。II组激动剂LY 354740（5和10 mg/kg）缓和PCP对DBA/2小鼠声惊吓前脉冲抑制的影响，但对C57 BL/6小鼠无影响。相比之下，两种NAAG肽酶抑制剂，ZJ 43（150 mg/kg）和2-PMPA（50，100和150 mg/kg），并没有显着影响PCP诱导的前脉冲抑制的减少在任何一个菌株。这些数据表明，在感觉运动处理的该模型中，II组激动剂的功效在小鼠中是品系特异性的。在DBA/2小鼠中II组激动剂和肽酶抑制剂的作用之间的差异可能与NAAG和激动剂对mGluR 2的功效差异有关。
Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder. The objective of this study was to re-examine the efficacy of a group II metabotropic glutamate agonist and NAAG peptidase inhibitors in prepulse inhibition models of schizophrenia across two strains of mice. The method used was an assay to determine the efficacy of these drugs in moderating the reduction in prepulse inhibition of acoustic startle in mice treated with PCP and D-amphetamine. The group II agonist LY354740 (5 and 10 mg/kg) moderated the effects of PCP on prepulse inhibition of acoustic startle in DBA/2 but not C57BL/6 mice. In contrast, two NAAG peptidase inhibitors, ZJ43 (150 mg/kg) and 2-PMPA (50, 100, and 150 mg/kg), did not significantly affect the PCP-induced reduction in prepulse inhibition in either strain. These data demonstrate that the efficacy of group II agonists in this model of sensory motor processing is strain-specific in mice. The difference between the effects of the group II agonist and the peptidase inhibitors in the DBA/2 mice may relate to the difference in efficacy of NAAG and the agonist at mGluR2.
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