Behavioral and biochemical effects of schizophrenomimetic drugs, phencyclidine and methamphetamine, in the rat

精神分裂拟态药物苯环己哌啶和甲基苯丙胺对大鼠的行为和生化影响

基本信息

批准号：
02670527
负责人：
NISHIKAWA Toru
金额：
$ 1.47万
依托单位：
National Institute of Neuroscience, National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

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 … More 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

为了进一步了解精神分裂症，精神分裂症，行为和生物化学作用的精神分裂症，行为和生化作用的药物疗法，精神分裂症药物的行为和生化expets，Phencyclidine（PCP）和甲基苯丙胺（MAP）（MAP），已在鼠中进行了研究。 PCP的系统性给药是N-Sethyl-D-天冬氨酸（NMDA）受体的非竞争力拮抗剂，以NMDA可逆的方式增加了额叶皮质中多巴胺（DA）代谢。对纹状体的影响很小。当选择性非竞争性（全身）和竞争性（局部给予额叶皮层）拮抗剂时，获得了相似的结果。 D-丙氨酸和D-丝氨酸（是NMDA受体的选择性变构激动剂）对PCP诱导的多动症，定型观念和共济失调的作用，以及地图诱导的运动刺激。 PCP和MAP的全身给药在…更多的大脑切片中引起了C-FOS样免疫反应性的差异模式，这表明两种药物激活的神经元电路的差异。最后，通过气相色谱法（GC），GC质量光谱法和高性能液相色谱法证明了荧光测定检测，从新生儿到老化时期大鼠的脑组织包含考虑的游离D-静脉内的数量，而血液样本中的D-氨基酸仅存在于痕量水平。本研究表明，PCP可能至少部分地阻断了NMDA受体介导的神经传递。还提出，NMDA受体瞄准镜参与由MAP引起的超塑料。这些发现进一步支持了以下假设：降低的兴奋性氨基酶传播可能与精神分裂症的病理生理有关。在这方面，研究内源性D-丝氨酸的功能作用以及NMDA受体变构激动剂的可能抗精神病性能。较少的