A pharmacological approach to the molecular basis of disturbed brain information processing of schizophrenia

精神分裂症症状出现在青春期之后，精神致病药物诱导精神分裂样精神病的能力也与年龄有关。此外，实验动物对致精神病药物的行为反应显然取决于出生后的发育。为了从发育的角度深入了解精神分裂症的分子基础，我们利用差异克隆技术和RT-PCR技术，在发育中的大鼠身上研究了类似精神分裂症的药物甲基苯丙胺(MAP：引起阳性症状的DA激动剂)和苯环利定(PCP：引起阳性和阴性症状的NMDA拮抗剂)对大脑基因表达的影响。我们在新大脑皮层A区发现了一个发育调节和MAP反应(Mrtl)或PCP反应(Prtl)基因，选择性的D1拮抗剂SCH23390可减弱MAP诱导的新皮质mrtl表达上调，而D2受体拮抗剂氟哌啶醇不能抑制PCP对prt1表达的上调。抗mrt1寡核苷酸阻断重复注射MAP产生反向耐受的能力(行为敏感化：精神分裂症阳性症状开始或复发的模型)。提示mrtl和prtl可能分别参与了精神分裂症阳性症状和阴性症状的病理生理过程。

Schizophrenic symptoms occur after adolescence and the ability of psychotogenic drugs to induce schizophrenia-like psychosis is also age-dependent. Moreover, the behavioral responses to psychotogenic drugs in experimental animals apparently depend upon postnatal development. To obtain insight into the molecular basis of schizophrenia from a developmental point of view, we investigated in the developing rats the effects of schizophrenomimetic drugs, methamphetamine (MAP : a DA agonist which causes positive symptoms) and phencyclidine (PCP : a NMDA antagonist which causes positive and negative symptoms), on gene expression in the brain using a differential cloning technique and RT-PCR. We identified a developmentally-regulated and MAP-responsive (mrtl) or PCP-responsive (prtl) gene in the neocortex A selective D1 antagonist SCH23390 attenuated a MAP-induced upregulation of neocortical mrtlexpression, while a D2-preferring antagonist haloperidol failed to inhibit the increasing effects of PCP on prtl expression. Anti-mrt1 oligonucleotide blocked the ability of repeated MAP injection to produce reverse tolerance (behavioral sensitization : a model of the onset or relapse of positive symptoms of schizophrenia). The present data suggest that mrtl or prtl might be involved in the pathophysiology of positive or negative symptoms of schizophrenia, respectively.