MIKUNI Masahiko Natl.Inst.Neurosci., Mental Disorder Res., Section Chief, 神経センター神経研究所・疾病研究第3部, 室長 (00125353)
熊代 新 国立精神, 神経センター神経研究所・疾病研究第3部, 大学院生
橋本 篤司 国立精神, 神経センター神経研究所・疾病研究第3部, 外来研究員
柏 淳 国立精神, 神経センター神経研究所・疾病研究第3部, 研究生
海野 麻未 国立精神, 神経センター神経研究所・疾病研究第3部, センター研究員
KASHIWA Atsushi Natl.Inst.Neurosci., Mental Disorder Res., Postdoc.
HASHIMOTO Atsushi Natl.Inst.Neurosci., Mental Disorder Res., Senior Reseacher
UMINO Asami Natl.Inst.Neurosci., Mental Disorder Res., Res.Associate
KUMASHIRO Shin Natl.Inst.Neurosci., Mental Disorder Res., Graduate Student
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¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1993 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1992 : ¥1,300,000 (Direct Cost : ¥1,300,000)
In order to get an insight into the possible dysregulation of cerebral neurotransmission and neural networks in schizophrenic disorders, we investigated the effects of schizophrenomimetic drugs including methamphetamine (MAP), cocaine and phencyclidine (PCP) on c-fos gene expression and dopamine (DA) metabolism in rat brain. Since D-serine, which has recently been shown to be an endogenous amino acid, antagonizes the psychotomimetic action of PCP and MAP in the rat, the anatomical distribution of the D-amino acid was examined in rat, mouse and human tissues.
Acute administration of MAP caused a widespread induction of nuclear c-Fos protein-like immunoreactivity in rat brain at 56-80 postnatal days. The greatest density of c-Fos positive cells was found in the pyriform cortex and olfactory tubercle followed by the II-VI layrs of the neocortex, septum, striatum, etc.In 8-day-old neonatal rats, acute MAP injection failed to cause c-fos expression in the II-V layrs of the neocortex, but ind
uced the proto-oncogene product in a deeper part of the layr VI of the neocortex, the paleocortex including the pyriform and the subcortical areas. MAP-induced c-Fos positive cells in the neocortex increased in number and distribution with postnatal development and showed the adult pattern after 21-23 postnatal days. In agreement with the results of immunohistochemical studies, Northen blot analysis revealed that, in the neocortex, a marked c-fos induction was observed after MAP injection at 21, 23, 25, 30 and 49 days postpartum, whereas the MAP treatment caused a low expression of the immediate early gene at 8 and 14 postnatal days. These distinct patterns of c-fos expression in the neocortical areas might reflect differences in responsive neuronal circuits to the drugs at the neonatal and young adult periods, because the effects of pharmacological, electrical and physiological stimuli have been considered to be traced by the prote-oncogene expression in the nervous system. Together with the observation that stimulant-induced sensitization occurs sometime after the third week of postnatal life, the present results, therefore, suggest that the maturation of certain neuronal circuits in the neocortex might be needed to develop behavioral sensitization to MAP and cocaine.
At 8 and 56 postnatal days, the distibution patterns of c-Fos positive cells after MAP were similar to those after DA agonists, cocaine and apomorphine, but clearly distinct from those after PCP and dizocilpine which are NMDA antagonists. Moreover, MAP markedly augmented extracellular DA release in the frontal cortex and striatum in a tetrodotoxin-insensitive manner in adult rats while PCP produced a frontal cortex-preferring and tetrodotoxin-sensitive increase in DA liberation. The differential effects of MAP and PCP could, in part, explain the differences between PCP-and MAP-induced psychosis.
An endogenous anti-PCP and-MAP substance D-serine was found to exclusively occur in brains with a persistent high content throughout life in the rat, mouse and human. The patterns of the regional variations in brain D-serine were closely correlated with those of the NMDA type glutamate receptor. Together with a selective stimuditribution of the NMDA-related glycine site by D-serine, these data suggest that the D-amino acid is a novel canditate as an intrinsic ligand for the glycine modulatory aite of the NMDA receptor and might be involved in pathophysiology of certain neuropsychiatric disorders including a subtype of schizophrenia. Less