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.

Neurotensin-1 (NT1) receptor agonists have been proposed as putative antipsychotic drugs. Recently brain penetrating NT analogues produced by stability enhancing modification of the smallest NT fragment, , have demonstrated antipsychotic-like efficacy after acute systemic injection in several preclinical animal tests predictive for antipsychotic efficacy. However, the evidence regarding the persistence versus tolerance of these effects after repeated administration is ambiguous. Previous studies have used compounds that non-selectively activated both NT1 and NT2 receptors, a factor which may have contributed to the ambiguity in findings regarding the emergence of tolerance. In this study, we investigated the effects of subchronic systemic administration of PD149163, a brain penetrating NT analogue with selectivity for the NT1 receptor, on amphetamineinduced locomotor activation, a classic preclinical test of antipsychotic-efficacy. Sprague Dawley rats were pretreated with eight consecutive daily subcutaneous (SC) injections of PD149163 or saline. On the ninth day rats received a pair of SC injections consisting of PD149163 or saline, followed by amphetamine (0.5mg/kg) or saline. Locomotor activity was then measured in photobeam equipped cages. The results indicated that repeated daily administration of PD149163 was able to antagonize amphetamine's locomotor activating effect comparable to that of the first dose, despite that repeated administration of PD149163 produced an increase in baseline locomotor activity not seen after the first dose. The results do not support development of tolerance for the acute antipsychotic-like effect of NT1 agonists and thus lend support to the contention that NT1 agonists are viable candidates as putative novel antipsychotic drugs.

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 analogue, on social discrimination in these rats. Adult rats were administered saline or one of 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-minute learning period. Animals were then housed individually for 30 minutes and then simultaneously exposed to the previously presented juvenile and a new juvenile for 4 minutes. 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.

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The neurotensin-1 (NT1) receptor has been implicated in mediating a number of important neurotensin effects. We have found that PD149163, a selective, brain penetrating, NT1 receptor agonist, produces a number of therapeutic-like preclinical effects after peripheral administration including pro-cognitive, antipsychotic and anxiolytic effects. In this study, we investigated PD149163's effect on food intake and thermal regulation, two physiological processes thought to be mediated by NT1 receptor. Brown Norway rats and leptin-deficient mice (ob/ob) mice were administered subcutaneous PD149163 (0, 0.1, 0.25, or 1 mg/kg) for ten consecutive days. Weight and 24-hour food intake were measured in mice and rats and core body temperature was also measured in rats. PD149163 significantly decreased food intake in rats and ob/ob mice and no tolerance was demonstrated to this effect over the course of the study. PD149163-treated animals exhibited weight loss compared to saline-treated animals. PD149163 produced hypothermia as expected but this effect did show tolerance over the course of the study, unlike feeding. The results suggest that NT1 receptor agonists are candidates for treatment of obesity and that somewhat different mechanisms are involved in NT1-induced feeding regulation and temperature regulation.