Schizophrenia and nitric oxide. Deficits in information processing investigated in animal models

Abstract

Rationale: Schizophrenia-like symptoms can be induced in humans by phencyclidine (PCP), a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. Schizophrenic patients and PCP-treated animals display deficits in pre-attentive information processing, as assessed by e.g. prepulse inhibition of the acoustic startle response. Recent studies have demonstrated that this deficit in prepulse inhibition, as well as other behavioural and neurochemical effects of PCP in rats, are blocked by nitric oxide synthase (NOS) inhibitors. This suggests an important role for NO in the effects of PCP. Objectives: The general aim of the present thesis was to investigate the involvement of NO in the psychotomimetic effects of PCP, or more specifically, in behaviours related to integration of sensory information in the central nervous system. Methods: Three behavioural paradigms in rodents with relevance to the clinical phenomenology were used. These paradigms were prepulse inhibition and habituation of acoustic startle, which are used to model the information processing deficit associated with schizophrenia, and locomotor activity, which is used to predict the tendency of a drug to elicit or exacerbate psychosis in humans. In addition, in vivo microdialysis and radioligand binding assays were used. Results: Systemic administration of PCP in mice caused a deficit in information processing, as assessed by prepulse inhibition and habituation of acoustic startle. These behavioural changes were normalized by pre-treatment with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Furthermore, the specific neuronal NOS inhibitor N ç-Propyl-L-arginine (L-NPA) blocked PCP-induced hyperlocomotion and deficits in prepulse inhibition. Contrary to these observations, the deficit in prepulse inhibition induced by MK-801, a more selective NMDA receptor antagonist than PCP, was unaffected by L-NAME pre-treatment in the rat. In addition, receptor-binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor-binding site did not show such an influence. In the in vivo microdialysis experiments a significant increase in cAMP levels, possibly indicating elevated NO production, was observed in the ventral hippocampus following both local infusion and systemic administration of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in this region. Furthermore, systemic administration of L-NAME attenuated the changes in cAMP levels and behavioural responses induced by PCP. Conclusions: In the present thesis further evidence was obtained that PCP causes schizophrenia-like changes in sensory information processing. Moreover, several behavioural and biochemical observations suggest that NO plays an important role in these effects. These findings open up new interesting vistas where drugs targeting the central NO production may be of therapeutic value in the treatment of schizophrenia. Indeed, some studies have implicated altered NO production in schizophrenia, but future studies are needed to elucidate its role in this disorder.