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

9比1。我们研究了神经活性类固醇对小鼠条件性恐惧应激(CFS)反应的影响，这种反应不能被典型的抗抑郁药物和抗焦虑药物减弱。硫酸脱氢表雄酮(DHEAS)和硫酸孕烯醇酮可减弱CFS反应，该作用可被Sigmal受体拮抗剂拮抗。与非应激小鼠相比，CFS反应小鼠脑内DHEAS含量减少，凋亡细胞数增加。这些发现提示神经类固醇激素的失衡和细胞凋亡的表达在CFS反应的表达中起着重要作用。我们用苯环利定(PCP)建立了精神分裂症阴性症状和认知障碍的动物模型，PCP在人类中产生精神分裂症样症状。五氯苯酚引起小鼠阴性症状样行为和认知功能障碍。我们发现PC…的负性症状样效应更多的P是通过前额叶皮质5-羟色胺、多巴胺和谷氨酸能系统的失衡来调节的。此外，五氯苯酚引起的认知障碍也可能与谷氨酸能系统的功能障碍有关，因为NMDA激动剂改善了五氯苯酚引起的认知缺陷。采用药物辨别实验检测了NMDA和Sigma受体相关药物对PCP辨别刺激效应的影响。NMDA拮抗剂，但不是西格玛受体激动剂，在训练来区分PCP和生理盐水的大鼠中产生PCP样的区别刺激效应。PCP的辨别刺激效应可被NMDA拮抗剂减弱，但不能被Sigma受体拮抗剂减弱。这些结果表明，NMDA受体参与了PCP的辨别性刺激效应。另一方面，DHEAS通过信号受体机制预防吗啡依赖的发展，而DHEAS的减弱作用被认为是通过ERK信号激活介导的c-fos表达调节所致。一氧化氮合酶(NO)抑制剂N-硝基-L-精氨酸甲酯和非竞争性N-甲基-D-甲基-D-天冬氨酸受体拮抗剂地佐西平分别损害小鼠和大鼠的空间工作记忆。这些损伤可被()-SKF-10,047和DHEAS所改善，其改善作用可被Sigmal受体拮抗剂拮抗。这些发现表明，Sigma受体参与了空间记忆形成所需的过程的调节。较少

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