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

1胜9负。我们研究了神经活性类固醇对小鼠条件恐惧应激（CFS）反应的影响，它与信号受体有亲和力，而典型的抗抑郁药和抗焦虑药不能减弱CFS反应。硫酸脱氢表雄酮（DHEAS）和硫酸孕烯醇酮（pregnenolone sulfate）可减弱CFS反应，其作用可被信号受体拮抗剂拮抗。CFS反应小鼠脑内DHEAS含量和凋亡细胞数量分别比非应激小鼠减少和增加。这些发现提示神经甾体和凋亡的表达失衡在CFS应答的表达中起重要作用。我们使用苯环利定（phencyclidine， PCP）建立了精神分裂症阴性症状和认知缺陷的动物模型，该药物在人体内产生类似精神分裂症的症状。PCP诱导小鼠负性症状样行为和认知缺陷。我们已经发现PC的负面症状效应…更多的P是由前额皮质中血清素能、多巴胺能和谷氨酸能系统的不平衡所介导的。此外，由于NMDA激动剂改善了pcp诱导的认知缺陷，pcp诱导的认知缺陷也可能与谷氨酸系统功能障碍有关。采用药物鉴别试验研究了NMDA和sigma受体相关药物对大鼠PCP鉴别刺激作用的影响。NMDA拮抗剂，而不是sigma受体激动剂，在训练大鼠区分PCP和生理盐水时产生PCP样的区分刺激效应。NMDA拮抗剂能减弱PCP的特异性刺激作用，而sigma受体拮抗剂则不能。这些发现表明NMDA受体参与了PCP的鉴别刺激作用。另一方面，DHEAS通过涉及信号受体的机制阻止吗啡依赖的发生，DHEAS的减弱作用可能与ERK信号激活介导的c-fos表达调节有关9-4。一氧化氮合酶抑制剂N^ g -硝基- l -精氨酸甲酯和非竞争性NMDA受体拮抗剂二唑西平分别对小鼠和大鼠的空间工作记忆造成损害。（+）- skf - 10,047和DHEAS可改善这些损伤，而信号受体拮抗剂可拮抗这种改善作用。这些发现表明，sigma受体参与了空间记忆形成所需过程的调节。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