Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated
schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in
schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg
haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of
haloperidol as well as the second-generation
antipsychotic,
clozapine, and the putative novel
antipsychotic,
PD149163, a
neurotensin mimetic that crosses the blood-brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of
haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of
clozapine and all the doses of
PD149163 tested reversed the PPI deficits in BB rats. In addition,
haloperidol, but not
clozapine or
PD149163 produced significant
catalepsy in BB rats, supporting the notion that
PD149163 has a profile consistent with atypical
antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of
antipsychotic efficacy and suggest that this model may differentiate between
antipsychotics belonging to different therapeutic categories, for example, first- and second-generation agents.