Lack of phencyclidine-induced effects in mice with reduced neuronal nitricoxide synthase

Rationale: Phencyclidine (PCP) is widely used as an animal model of schizop hrenia, because in humans it can induce positive and negative symptoms asso ciated with schizophrenia. PCP is an antagonist of N-methyl-D-aspartate rec eptors, which are associated with the nitric oxide (NO) system. Objective a nd methods: The primary objective was to determine whether neuronal NO synt hase (nNOS) is involved in PCP-induced behaviours and neuronal activation, as measured by the expression of c-Fos. After characterizing a PCP mouse mo del (dose-response study, Experiment 1), we measured PCP-induced effects in mice treated with nNOS antisense oligodeoxynucleotides (AS-ODNs) (Experime nt 2), and in nNOS knockout (nNOS(-/-)) mice (Experiment 3). Results: PCP 5 mg/kg induced the maximum behavioural effects of all doses tested, consist ing of hyperlocomotion, stereotyped turning behaviour, without the presence of ataxia. PCP also induced an increase in Fos-like immunoreactivity (Fos- LIR) in the frontal cortex, as well as in the midline limbic (thalamic and hypothalamic nuclei) areas. In the AS-ODN-treated mice, PCP induced less be haviour when compared to water-treated controls. In the nNOS-/- mice, PCP i nduced less behaviour and a decrease in Fos-LIR in the frontal cortex and m idline limbic areas, when compared to wildtype littermate controls. Conclus ions: Our findings suggest that the frontal cortex and midline thalamic bra in regions are involved in PCP-induced effects in mice. Furthermore, we sho w that an intact nNOS system is necessary to obtain PCP-induced effects. Th is may implicate nNOS as a viable drug target in the treatment of schizophr enia.