Blockade of phencyclidine-induced effects by a nitric oxide donor

摘要: Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim this study was to better understand the role nitric oxide (NO) in mechanism action PCP and determine whether positive NO modulators may provide a new approach treatment schizophrenia. The effects donor, sodium nitroprusside (SNP), were studied PCP-treated rats. Following drug administration, behavioural changes expression c-fos, metabolic marker functional pathways brain, simultaneously monitored. Acute (5 mg kg−1, i.p.) induced complex syndrome, consisting hyperlocomotion, stereotyped behaviours ataxia. Treatment with SNP (2–6 mg kg−1, by itself produced no effect on any behaviour but completely abolished PCP-induced dose- time-dependent manner. PCP had differential regional c-fos rat suggesting regionally different patterns neuronal activity. most prominent immunostaining observed cortical regions. Pre-treatment blocked at doses similar those that suppress effects. These results implicate system PCP. fact suggests drugs targeting glutamate-NO represent novel psychosis schizophrenia. Keywords: Phencyclidine, oxide, nitroprusside, locomotor activity, ataxia, rat Introduction Schizophrenia one serious human brain diseases, yet its aetiology pathophysiology remain largely unknown. For past 25 years it has been assumed schizophrenia from chronic dopamine hyperactivity (Seeman et al., 1976; Meltzer & Stahl, 1976). However, antagonists are relatively ineffective alleviating some symptoms schizophrenia, involvement other systems disease. In addition their limited efficacy, currently available often produce severe side effects, major source non-compliance. There is, therefore, need for approaches psychiatric disorder. proposed be best pharmacological models because can mimic full spectrum schizophrenic disorders (Toru 1994; Steinpreis, 1996; Thornbert Saklad, Jentsch 1997; Moghaddam Adams, 1998). Thus, felt investigating central might help us both explore efficacy antipsychotic drugs. model, ability compound antagonise specific animals would predictive properties humans. very complex. Although interacts various strongly implicated Thornberg 1996), potent glutamatergic system. blocks actions glutamate N-methyl-D-aspartate (NMDA) receptors, giving support hypoglutamatergic theory Tamminga, Glutamate, acting through NMDA appears principal activation signal production (Ignarro Murad, 1995; Szabo, 1996). therefore expected decrease levels; restoring levels reverse effect. Consistent idea, shown directly inhibit synthase (NOS) activity (Osawa Davila, 1993; Chetty 1995) have synergistic NOS inhibitor, L-NG-nitroarginine methyl ester (L-NAME) (Noda Bujas-Bobanovic 1998b). light data seemed interest test idea via oxide. purpose, we donor (SNP) immediate-early gene product, c-fos.