title: Nitric oxide synthase inhibitors improve prepulse inhibition responses of Wistar rats.
abstract: BACKGROUND
  Cognitive and attentional deficits in schizophrenia include impairment of the sensorimotor filter as measured by prepulse inhibition (PPI). In this way, the study of animals that naturally present low PPI responses could be a useful approach for screening new antipsychotic drugs. Several pieces of evidence suggest that dopamine and nitric oxide (NO) can modulate PPI but their role in those animals is unknown.
  
  
  OBJECTIVE
  The aim of this study was to investigate the role of dopamine and NO in Wistar rats with naturally low PPI response.
  
  
  METHODS
  Male Wistar rats with low PPI responses received an i.p. injection of the antipsychotics haloperidol (0.1, 0.3 or 1mg/kg) or clozapine (0.5, 1.5 or 5mg/kg), the anxiolytic diazepam (1 or 3mg/kg) or the NO synthase (NOS) inhibitors, N(G)- nitro-l-arginine (l-NOARG; 40mg/kg, acutely or sub-chronically) or 7-Nitroindazole (7-NI; 3, 10 or 30mg/kg). All animals were submitted to the PPI test 1h after injection. Striatal and cortical dopamine, DOPAC, and noradrenaline levels of rats with low PPI responses were compared to rats with normal PPI responses.
  
  
  RESULTS
  We found increased levels of catecholamines on the striatum and prefrontal cortex of Wistar rats with low PPI. In these animals, both antipsychotics, typical and atypical, and NOS inhibitors significantly increased PPI.
  
  
  CONCLUSIONS
  Taken together, our findings suggest that the low PPI phenotype may be driven by an overactive catecholamine system. Additionally, our results corroborate the hypothesis of dopamine and NO interaction on PPI modulation and suggest that Wistar rats with low PPI may represent an interesting non-pharmacological model to evaluate new potential antipsychotics.
authors.affiliation: Department of Pharmacology, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Issy
authors.forename: M
authors.initials: M
authors.lastname: Lazzarini
authors.forename: R E
authors.initials: RE
authors.lastname: Szawka
authors.forename: R O G
authors.initials: RO
authors.lastname: Carolino
authors.forename: J A
authors.initials: JA
authors.lastname: Anselmo-Franci
authors.forename: E A
authors.initials: EA
authors.lastname: Del Bel
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D007266:Inhibition, Psychological; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D015306:Biogenic Monoamines; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007191:Indazoles; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D006220:Haloperidol; D003975:Diazepam; C080122:7-nitroindazole