JEANーMARC Ka 国立保健医学研究所, CNRS研究部長
ISABELLE Cha 国立保健医学研究所, 研究員
TANGUI Mauri 国立保健医学研究所, 研究員
ALAIN Privat 国立保健医学研究所, 国立化学高等学院, 研究部長
HIRAMATSU Masayuki Faculty of Pharmaceutical Sciences, Meijo University, Research Associate, 薬学部, 助手 (10189863)
YAMADA Kiyofumi School of Medicine, Nagoya University, Associate Professor, 医学部, 助教授 (30303639)
|Budget Amount *help
¥14,900,000 (Direct Cost : ¥14,900,000)
Fiscal Year 2000 : ¥5,100,000 (Direct Cost : ¥5,100,000)
Fiscal Year 1999 : ¥5,200,000 (Direct Cost : ¥5,200,000)
Fiscal Year 1998 : ¥4,600,000 (Direct Cost : ¥4,600,000)
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
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.