A neurodevelopmental pharmacological approach to the molecular pathophysiology of schizophrenic symptoms

精神分裂症的症状通常发生在青春期之后，并且精神药物诱导精神分裂症样精神病的能力也与年龄有关。此外，精神分裂症的药理学模型的实验动物拟精神分裂症药物的行为反应显然取决于出生后的发展。精神分裂症的晚期发展表现及其模型表明，精神分裂症中受损的分子级联仅在人类青春期或实验动物中特定级联可能成熟的关键时期后才能受到拟精神分裂症药物的影响或对拟精神分裂症药物有反应。为了深入了解与精神分裂症发育特征相关的分子，我们在发育中的大鼠中研究了拟精神分裂症药物甲基苯丙胺的作用。（MAP：一种DA激动剂，可引起精神分裂症样阳性症状）和苯环利定（五氯苯酚：引起精神分裂症样阳性和阴性症状的NMDA拮抗剂），利用差异克隆技术和RT-PCR技术，我们进一步研究了药理学概况和人类同源物先前确定的发育调控和MAP-响应（mrt 1）或PCP-响应（prt 1）基因在新皮层。此外，我们分离出新的候选人精神分裂症相关基因，mrt 3和prt 4从neocrtex。

Schizophrenic symptoms typically occur after the adolescence and the ability of psychotogenic drugs to induce schizophrenia-like psychosis is also age-dependent. Moreover, the behavioral responses to schizophrenomimetic drugs in experimental animals as pharmacological models of schizophrenia apparently depend upon postnatal development. The late developing manifestation of schizophrenia and its models suggest that the molecular cascades impaired in schizophrenia could be affected by or responsive to schizophrenomimetics only after the adolescence in humans or the critical period in experimental animals when the specific cascades might maturate. To obtain insight into the molecules that are specifically related to schizophrenia based upon the developmental features, we investigated in the developing rats the effects of schizophrenomimetic drugs, methamphetamine (MAP : a DA agonist which causes the schizophrenia-like positive symptoms) and phencyclidine (PCP : a NMDA antagonist causing schizophrenia-like positive and negative symptoms), on gene expression in the brain using a differential cloning technique and RT-PCR. We further studied the pharmacological profiles and the human homologues of previously identified a developmentally-regulated and MAP-responsive (mrt1) or PCP-responsive (prt1) gene in the neocortex In addition, we isolated the novel candidates for schizophrenia-related genes, mrt3 and prt4 from the neocrtex.