Molecular mechanisms of schizophrenic symptoms

兴奋剂诱导的行为致敏（反向耐受）被认为是精神分裂症复发易感性的实验模型。急性注射甲基苯丙胺（MAP）、可卡因、诺非芬等致敏诱导剂可引起大鼠背内侧、岛叶前额叶皮层和梨状皮质组织纤溶酶原激活物（TPA） mRNA的短暂和剂量依赖性诱导。D1和D2多巴胺拮抗剂可显著抑制TPA mRNA的map诱导，这些拮抗剂已被证明可拮抗精神兴奋剂产生行为致敏的能力。此外，应用荧光示踪剂氟金逆行标记表达TPA mRNA的皮质细胞，内侧纹状体内，而非外侧纹状体内和丘脑内。这些结果表明，皮质纹状体通路亚群可能与一组精神分裂症的行为致敏和/或病理生理学的发展有关。在大鼠皮层中，我们发现了由苯环利定（PCP）诱导的神经元活动标记物c-Fos分布模式的发育变化，该标记物可引起类似精神分裂症的阳性和阴性症状。这些变化可能反映了在PCP精神病和/或精神分裂症亚群中可能受到干扰的皮层网络子集的成熟过程。为了进一步探索与精神分裂症症状相关的候选基因，我们试图通过RNA任意引物PCR寻找对MAP或PCP有特异性反应的新基因。

Stimulant-induced behavioral sensitization (reverse tolerance) has been considered to be an experimental model of susceptibility to recurrence of schizophrenia Acute injection of sensitization-inducing agents including methamphetamine (MAP), cocaine, nomifensine caused a transient and dose-dependent induction of tissue plasminogen activator (TPA) mRNA in the dorsomedial and insular prefrontal cortex and the piriformcortex of the rat. MAP-induction of TPA mRNA was markedly inhibited by D1 and D2 dopamine antagonists which have been shown to antagonize the ability of psychostimulants to develop behavioral sensitization. Moreover, intra-medial striatum, but not intra-lateral striatum and intra-thalamic, application of a fluorescent tracer, fluorogold, retrogradely labeled the cortical cells expressing TPA mRNA.These results suggest that a subpopulation of cortico-striatal pathways could be implicated in the development of behavioral sensitization and/or the pathophysiology of a group of shizophrenia. In the rat cortex, we have found the developmental changes in the distribution patterns of a neuronal activity marker, c-Fos, induced by phencyclidine (PCP) that causes schizophrenia-like positive and negative symptoms. These changes might reflect the maturation process of a subset of the cortical networks which could be disturbed in PCP psychosis and/or a subgroup of shizophrenia. To further explore the candidate genes related to schizophrenic symptoms, we have tried to find novel genes that specifically response to MAP or PCP by using RNA arbitrarily primed PCR.