title: Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase.
abstract: BACKGROUND
  Phencyclidine (PCP) is widely used as an animal model of schizophrenia, because in humans it can induce positive and negative symptoms associated with schizophrenia. PCP is an antagonist of N-methyl-D-aspartate receptors, which are associated with the nitric oxide (NO) system.
  
  
  OBJECTIVE
  The primary objective was to determine whether neuronal NO synthase (nNOS) is involved in PCP-induced behaviours and neuronal activation, as measured by the expression of c-Fos. After characterizing a PCP mouse model (dose-response study, Experiment 1), we measured PCP-induced effects in mice treated with nNOS antisense oligodeoxynucleotides (AS-ODNs) (Experiment 2), and in nNOS knockout (nNOS-/-) mice (Experiment 3).
  
  
  RESULTS
  PCP 5 mg/kg induced the maximum behavioural effects of all doses tested, consisting 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 behaviour when compared to water-treated controls. In the nNOS-/- mice, PCP induced less behaviour and a decrease in Fos-LIR in the frontal cortex and midline limbic areas, when compared to wild-type littermate controls.
  
  
  CONCLUSIONS
  Our findings suggest that the frontal cortex and midline thalamic brain regions are involved in PCP-induced effects in mice. Furthermore, we show that an intact nNOS system is necessary to obtain PCP-induced effects. This may implicate nNOS as a viable drug target in the treatment of schizophrenia.
authors: Dalhousie University, Department of Pharmacology, Halifax, Nova Scotia, Canada.
authors: D C
authors: DC
authors: Bird
authors: M
authors: M
authors: Bujas-Bobanovic
authors: H A
authors: HA
authors: Robertson
authors: S M
authors: SM
authors: Dursun
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016376:Oligonucleotides, Antisense; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D010622:Phencyclidine