Cognitive function studied in animal models of schizophrenia

Cognitive function studied in animal models of schizophrenia Cognitive dysfunction is considered a core deficit of schizophrenia, which currently lacks effective pharmacological treatment. In order to identify novel and more effective drug treatments, translational experimental animal models of cognitive dysfunction are required. Schizophrenia-like symptoms can be induced in humans by phencyclidine (PCP). PCP also induces schizophrenia-like behavioural changes in experimental animals and several of these effects can be ameliorated by pre-treatment with nitric oxide (NO) synthase inhibitors. This suggests an important role of NO in the effects of PCP. The general aim of the present thesis was to further investigate the effects of PCP, and the role of NO in these effects, in translational experimental animal models of cognitive dysfunction. Three behavioural models in rodents with relevance to schizophrenia were used. Pre-attentive information processing and non-associative learning were studied using the prepulse inhibition and habituation of the acoustic startle response models respectively. Additionally, selective attention was investigated using latent inhibition in taste aversion conditioning. Systemic administration of PCP to mice caused a deficit in habituation of the acoustic startle response. This effect of PCP was attenuated by pre-treatment with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Furthermore, systemic administration of PCP potentiated latent inhibition in taste aversion conditioning. This effect could be normalized by pre-treatment with L-NAME. Finally, acute and sub-chronic inhibition of NO substrate (L-arginine) availability, using the amino acid L-lysine, attenuated the deficit in prepulse inhibition induced by PCP. In the present thesis PCP was shown to induce deficits in three translational animal models of cognitive dysfunction associated with schizophrenia. Additionally, blocking NO production ameliorated the deficits induced by PCP. These findings lend further support to the notion that drugs targeting central NO production could be of therapeutic value in the treatment of cognitive dysfunction in schizophrenia. In addition, they indicate that L-arginine availability may be an important regulatory mechanism of NO production in the brain. 3 This thesis is based on the following papers, which will be referred to in the text by their Roman numerals; I. Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms. II. The effects of phencyclidine on latent inhibition in taste aversion conditioning: differential effects of preexposure and conditioning. IV. The amino acid, L-lysine, blocks the disruptive effect of phencyclidine on prepulse inhibition in mice.