| Co-Investigator(Kenkyū-buntansha) |
MIKUNI Masahiko Div. of Mental Disorder Res., Natl. Inst. of Neurosci., Section Chief, 神経センター・神経研究所・疾病研究第三部, 室長 (00125353)
TAKAHASHI Kiyohisa Div. of Mental Disorder Res., Natl. Inst. of Neurosci., Director, 神経センター・神経研究所・疾病研究第三部, 部長 (30073076)
UMINO Asami Div. of Mental Disorder Res., Natl. Inst. of Neurosci., Researcher
HASHIMOTO Atsushi Div. of Mental Disorder Res., Natl. Inst. of Neurosci., Researcher
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| Research Abstract |
In order to get further insights into the pathophysiology and the possible pharmacotherapy of schizophrenia, behavioral and biochemical effets of schizophrenominetic drugs, phencyclidine (PCP) and methamphetamine (MAP), have been investigated in the rat. Systemic administration of PCP, which is a non-competitive antagonist of N-sethyl-D-aspartate (NMDA) receptor, incresed dopamine (DA) metabolism in the frontal cortex in a NMDA-reversible manner. with little influence on that in the striatum. Similar results were obtained when selective non-competitive (given systemically) and competitive (given locally into the frontal cortex) antagonists were administered. Intra-cerebroventricular application of D-alanine and D-serine (which are selective allosteric agonists for NMDA receptor) antagonized the PCP-induced hyperactivity, stereotypy and ataxia, and the MAP-induced locomotor stimulation. Systemic administration of PCP and MAP caused differential patterns of c-Fos-like immunoreactivity in
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the brain slices, suggesting the diffences in neuronal circuits activated by the two drugs. Finally, it is demonstrated by gas chromatography (GC), GC-mass spectrometry and high-performance liquid chromatography with fluorometric detection that the brain tissues of rats from neonatal to aged periods contain considerable amount of free D-serine whereas the D-amino acid in the blood samples is present only in trace level. The present study indicates that PCP may elicit hyperdopaminergic activity and abnormal behaviors by, at least in part, blockade of NMDA receptor-mediated neurotransmission. It is also suggested that NMDA receptor sight be involved in hyperlocomotion caused by MAP. These findings add a further support to the hypothesis that reduced excitatory amino acidergic transmission could be implicated in the pathophysiology of schizophrenia. In this aspect, it is of interest to investigate the functional roles of endogenous D-serine and the possile anti-psychotic properties of allosteric agonists of NMDA receptor. Less
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