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

为了进一步了解精神分裂症的病理生理学和可能的药物治疗方法，我们在大鼠身上研究了精神分裂症药物苯环利定（PCP）和甲基苯丙胺（MAP）的行为和生化作用。PCP是一种n-乙基- d -天冬氨酸（NMDA）受体的非竞争性拮抗剂，全身给药可以以NMDA可逆的方式增加额叶皮层的多巴胺（DA）代谢。对纹状体的影响很小。选择性非竞争性拮抗剂（全身给予）和竞争性拮抗剂（局部给予额叶皮质）也获得了类似的结果。脑室内应用d -丙氨酸和d -丝氨酸（它们是NMDA受体的选择性变构激动剂）可拮抗pcp诱导的多动、刻板印象和失调以及map诱导的运动刺激。全身给药PCP和MAP在更多的脑切片中引起c- fos样免疫反应的不同模式，表明两种药物激活的神经回路存在差异。最后，通过气相色谱（GC）、气相色谱-质谱和高效液相色谱荧光检测证明，从新生期到老年期的大鼠脑组织中含有相当数量的游离d -丝氨酸，而血液样品中的d -氨基酸仅以微量水平存在。目前的研究表明，PCP可能通过至少部分阻断NMDA受体介导的神经传递而引起高多巴胺能活性和异常行为。NMDA受体可能参与了MAP引起的运动过度。这些发现进一步支持了兴奋性氨基酸能传递减少可能与精神分裂症病理生理有关的假设。在这方面，研究内源性d -丝氨酸的功能作用和NMDA受体变构激动剂可能的抗精神病特性是很有意义的。少

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