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

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.

Figure 1

Illustration of the Social Discrimination Paradigm. Adult rats acclimate in the social discrimination box for 20 minutes. Following this acclimation period, the learning trial begins with the adult rat exposed to a juvenile rat for 4 minutes. The adult rat is then returned to its home cage for 30 minutes. During the retrieval trial the adult animal returns to the chamber with the introduction of a new juvenile along with the same juvenile from the learning trial for 4 minutes. The positions of the juveniles are randomly alternated

Figure 2

The effects of saline (n=20), PD149163 and clozapine (n = 7-8 per dose) on the Discrimination Index in LE rats. Discrimination Index equals (time spent investigating new juvenile - time spent investigating familiar juvenile) / (time spent investigating new juvenile + time spent investigating familiar juvenile). Significantly higher than saline is represented by * (P< 0.05).

Figure 3

The effects of saline (n = 36), PD149163 and clozapine (n = 11-15 per dose) on the Discrimination Index in BRAT rats. Discrimination Index equals (time spent investigating new juvenile - time spent investigating familiar juvenile) / (time spent investigating new juvenile + time spent investigating familiar juvenile). Significantly higher than saline is represented by * (P< 0.05) and ** (P< 0.01).