A neurodevelopmental pharmacological approach to the molecular pathophysiology of schizophrenic symptoms

精神分裂症症状通常发生在青春期之后，精神源性药物诱导精神分裂症样精神病的能力也与年龄有关。此外，作为精神分裂症药理学模型的实验动物对精神分裂症模拟药物的行为反应显然依赖于出生后的发育。精神分裂症的晚期表现及其模型表明，精神分裂症中受损的分子级联只有在人类的青春期或实验动物的特定级联可能成熟的关键时期之后才可能受到精神分裂症模拟物的影响或对其有反应。为了根据发育特征深入了解与精神分裂症特异性相关的分子，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（MAP：一种导致精神分裂症样阳性症状的DA激动剂）和苯环利定（PCP：一种导致精神分裂症样阳性和阴性症状的NMDA拮抗剂）对大脑中基因表达的影响。我们进一步研究了新皮质中先前鉴定的发育调节和MAP-responsive （mrt1）或PCP-responsive （prt1）基因的药理学特征和人类同源物。此外，我们从新皮质中分离出新的候选精神分裂症相关基因，mrt3和prt4。

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.