The brattleboro rat displays a natural deficit in social discrimination that is restored by clozapine and a neurotensin analog

Neuropsychopharmacology. 2009 Jul;34(8):2011-8. doi: 10.1038/npp.2009.15. Epub 2009 Mar 25.

Abstract

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Clozapine / pharmacology*
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Male
  • Mental Disorders / drug therapy*
  • Mental Disorders / etiology
  • Mental Disorders / physiopathology
  • Neurotensin / agonists*
  • Neurotensin / analogs & derivatives
  • Neurotensin / metabolism
  • Neurotensin / pharmacology
  • Rats
  • Rats, Brattleboro
  • Rats, Long-Evans
  • Receptors, Neurotensin / agonists
  • Receptors, Neurotensin / metabolism
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Schizophrenic Psychology
  • Social Behavior*

Substances

  • Antipsychotic Agents
  • PD 149163
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • Neurotensin
  • Clozapine