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

西格玛受体在神经心理疾病动物模型中的作用。

基本信息

批准号：
08457027
负责人：
NABESHIMA Toshitaka
金额：
$ 4.74万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

9-1. We examined the effects of sigma receptor-related agents on conditioned fear stress (CFS) response that could not be attenuated by typical antidepressants and anxiolytics in mice. The activation of phenytoin-sensitive sigma1 receptors which are closely connected to the meso-limbic dopaminergic systems was demonstrated to be involved in the ameliorating effects of (+) -SKF-10,047 and dextromethorphan, sigma1 receptor agonists on the CFS response. Dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate, neurosteroids that have an affinity for sigma1 receptors, also attenuated the CFS response. The DHEAS concentration in the serum of mice showing CFS response was lower than that in the non-stressed mice. These findings suggested that neurosteroids play an important role in the expression of CFS response.9-2. We developed the animal model for negative symptom in schizophrenia using phencyclidine (POP), which produces schizophrenic-like symptom in human, and examined the effect … More s of sigma receptor-related agents on PCP-induced negative symptom-like action. (+) -SKF-10,047 as well as PCP induced negative symptom-like action in mice. Sigma receptor antagonists did not attenuate the PCP-induced negative symptom-like action. Although sigma receptors may be involved in expression of PCP-induced negative symptom-like action, it is unlikely that sigma receptor antagonists are candidates of potential therapeutic drug for negative symptoms in schizophrenia.9-3. We examined the effects of sigma receptor-related agents on the discriminative stimulus effects of PCP in rats using drug discrimination test. Sigma receptor agonists did not produce PCP-like discriminative stimulus effects in rats trained to discriminate PCP from saline. The discriminative stimulus effects of PCP were not attenuated by sigma receptor antagonists. These findings suggested that sigma receptors were not involved in the discriminative stimulus effects of PCP.9-4. N^G-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor and dizocilpine, non-competitive NMDA receptor antagonist, impaired the spatial working memory in mice and rats, respectively. These impairments were ameliorated by (+) -SKF-10,047, the ameliorating effect being antagonized by NE-lO0. These findings suggested that sigma receptors were involved in the regulation of processes required for spatial memory formation. Less

9-1.我们研究了西格玛受体相关药物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和抗焦虑药减弱。与中脑边缘多巴胺能系统密切相关的苯妥英敏感性 sigma1 受体的激活被证明参与 (+) -SKF-10,047 和右美沙芬、sigma1 受体激动剂对 CFS 反应的改善作用。硫酸脱氢表雄酮 (DHEAS) 和硫酸孕烯醇酮是对 sigma1 受体具有亲和力的神经类固醇，也能减弱 CFS 反应。显示 CFS 反应的小鼠血清中 DHEAS 浓度低于未应激小鼠。这些发现表明神经类固醇在 CFS 反应的表达中发挥重要作用。9-2。我们使用苯环己哌啶（POP）开发了精神分裂症阴性症状的动物模型，该药物在人类中产生类似精神分裂症的症状，并检查了西格玛受体相关药物对五氯苯酚诱导的阴性症状样作用的影响。 (+)-SKF-10,047 以及 PCP 在小鼠中诱导阴性症状样作用。 Sigma 受体拮抗剂不会减弱 PCP 诱导的阴性症状样作用。尽管σ 受体可能参与PCP 诱导的阴性症状样作用的表达，但σ 受体拮抗剂不太可能成为治疗精神分裂症阴性症状的潜在治疗药物。9-3。我们使用药物辨别试验检查了西格玛受体相关药物对大鼠 PCP 辨别刺激作用的影响。在训练区分五氯苯酚和盐水的大鼠中，Sigma 受体激动剂不会产生类似五氯苯酚的辨别刺激作用。西格玛受体拮抗剂不会减弱 PCP 的辨别刺激作用。这些发现表明 sigma 受体不参与 PCP.9-4 的辨别刺激作用。一氧化氮 (NO) 合酶抑制剂 N^G-硝基-L-精氨酸和非竞争性 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。这些损伤被(+)-SKF-10,047改善，改善效果被NE-100拮抗。这些发现表明西格玛受体参与空间记忆形成所需过程的调节。较少的