Molecular mechanisms of schizophrenic symptoms

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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.