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Role of NMDA and sigma receptors in the animal models for neuropsychological diseases.

NMDA 和 sigma 受体在神经心理疾病动物模型中的作用。

基本信息

批准号：
10044260
负责人：
NABESHIMA Toshitaka
金额：
$ 9.54万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

9-1. We examined the effects of neuroactive steroids, which have an affinity for sigmal receptors, on conditioned fear stress (CFS) response that could not be attenuated by typical antidepressants and anxiolytics in mice. Dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate attenuated the CFS response, the effects being antagonized by sigmal receptor antagonist. The DHEAS contents and number of apoptotic cells in the brain of mice showing CFS response were decrease and increase, respectively, compared to those in the non-stressed mice. These findings suggest that the imbalance of neurosteroids and expression of apoptosis play an important role in the expression of CFS response.9-2. We developed the animal model for negative symptom and cognitive deficit in schizophrenia using phencyclidine (PCP), which produces schizophrenia-like symptom in human. PCP induced negative symptom-like action and cognitive deficit in mice. We have found that the negative symptom-like effect of PC … More P is mediated by imbalance of serotonergic, dopaminergic and glutamatergic systems in the prefrontal cortex. Further, PCP-induced cognitive deficit also may be involved in dysfunction of glutamatergic systems since NMDA agonists improved PCP-induced cognitive deficit.9-3. We examined the effects of NMDA and sigma receptor-related agents on the discriminative stimulus effects of PCP in rats using drug discrimination test. NMDA antagonist, but not sigma receptor agonists, produced PCP-like discriminative stimulus effects in rats trained to discriminate PCP from saline. The discriminative stimulus effects of PCP were attenuated by NMDA antagonist, but not by sigma receptor antagonists. These findings suggest that NMDA receptors are involved in the discriminative stimulus effects of PCP.On the other hand, DHEAS prevented the development of morphine dependence through mechanism involving sigmal receptors, and the attenuating effect of DHEAS is suggested to result from the regulation of c-fos expression mediated by ERK signaling activation.9-4. N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor and dizocilpine, non-competitive NMDA receptor antagonist, impaired spatial working memory in mice and rats, respectively. These impairments were ameliorated by (+)-SKF-10, 047 and DHEAS, the ameliorating effects being antagonized by sigmal receptor antagonist. These findings suggest that sigma receptors are involved in the regulation of processes required for spatial memory formation. Less

9-1.我们研究了神经活性类固醇的影响，这对sigmal受体具有亲和力，对条件性恐惧应激（CFS）反应，不能被典型的抗抑郁药和抗焦虑药在小鼠中衰减。硫酸脱氢表雄酮（DHEAS）和硫酸双烯醇酮可减弱CFS反应，其作用可被σ 1受体拮抗剂所拮抗。与非应激组相比，CFS反应组小鼠脑内DHEAS含量减少，凋亡细胞数增加。这些发现表明，神经类固醇的失衡和细胞凋亡的表达在CFS反应的表达中起重要作用。本研究利用苯环己哌啶（PCP）建立了精神分裂症阴性症状和认知功能障碍的动物模型。五氯苯酚可诱导小鼠产生负性类神经元样行为和认知缺陷。我们发现，PC的负向类神经元效应 ...更多信息 P是由前额叶皮层中的多巴胺能、多巴胺能和多巴胺能系统的不平衡介导的。此外，PCP诱导的认知缺陷也可能涉及神经元能系统的功能障碍，因为NMDA激动剂改善PCP诱导的认知缺陷。本实验采用大鼠药物辨别实验，观察了NMDA和σ受体相关物质对PCP辨别刺激效应的影响。NMDA拮抗剂，而不是sigma受体激动剂，产生PCP样的歧视性刺激效应，训练大鼠区分PCP盐水。PCP的辨别性刺激效应可被NMDA受体拮抗剂减弱，而σ受体拮抗剂则不减弱。这些发现表明NMDA受体参与PCP的辨别性刺激效应。另一方面，DHEAS通过涉及sigmal受体的机制防止吗啡依赖的发展，并且DHEAS的减弱效应被认为是由ERK信号传导激活介导的c-fos表达调节引起的。9 -4.一氧化氮（NO）合酶抑制剂N^G-硝基-L-精氨酸甲酯和非竞争性NMDA受体拮抗剂地佐环平分别损害小鼠和大鼠的空间工作记忆。（+）-SKF-10，047和DHEAS可改善上述损伤，σ 1受体拮抗剂可拮抗上述改善作用。这些发现表明，σ受体参与调节空间记忆形成所需的过程。少