1998 Fiscal Year Final Research Report Summary
Role of sigma receptors in the animal models for neuropsychological diseases.
| Project/Area Number |
08457027
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Nagoya University |
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Principal Investigator |
NABESHIMA Toshitaka School of Medicine, Nagoya University, Professor, 医学部, 教授 (70076751)
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| Co-Investigator(Kenkyū-buntansha) |
HASEGAWA Takaaki School of Medicine, Associate Professor, 医学部, 教授 (80198720)
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| Project Period (FY) |
1996 – 1998
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| Keywords | Sigma receptors / Neurostereoids / Stress / Schizophrenia / Drug dependence / Learning and memory |
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| Research Abstract |
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
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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
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