Reversal of Sensorimotor Gating Deficits in Brattleboro Rats by Acute Administration of Clozapine and a Neurotensin Agonist, but not Haloperidol: a Potential Predictive Model for Novel Antipsychotic Effects

Abstract

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.

Disruption of the Prepulse Inhibition of the Startle Reflex in Vasopressin V1b Receptor Knockout Mice: Reversal by Antipsychotic Drugs

“…Although the association between startle response and PPI is not currently clear, our present findings support the possibility that V1bR regulates the PPI of the startle reflex. Interestingly, Brattleboro rats, in which the ability to synthesize AVP is impaired, have been reported to exhibit deficits of PPI of the startle reflex and a high startle response (Feifel and Priebe, 2001;Feifel et al, 2004). Moreover, individual startle responses and PPI in these rats were not correlated like in our current results.…”

“…Thus, to normalize PPI deficits, atypical antipsychotics such as risperidone and clozapine probably interact with the brain systems of V1bR KO mice. Interestingly, the PPI deficits observed in Brattleboro rats were also reversed by acute administration of clozapine but not by acute administration of haloperidol (Feifel et al, 2004). These findings suggest that these deficits might be particularly sensitive to some critical properties of those antipsychotic drugs.…”

“…Recently, Brattleboro rats, in which the ability to synthesize AVP is impaired, have been reported to exhibit deficits of PPI of the startle reflex (Feifel and Priebe, 2001;Feifel et al, 2004). It is possible that central AVP may play an important role in the regulation of PPI.…”

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

“…2A), suggesting the requirement of NTS1 receptors. Because PD149163 is a small-molecule NTS1 agonist that crosses the blood-brain barrier (Feifel et al, 2004(Feifel et al, , 2010Azmi et al, 2006), we tested the effects of PD149163 on neuronal excitability recorded from stellate neurons in the EC. Bath application of PD149163 (0.25 M) robustly increased the AP firing frequency (n ϭ 10, p ϭ 0.002; Fig.…”

Differential sensitivity of the Brattleboro rat to glutamatergic and dopaminergic perturbation

“…Moreover, there is evidence that VP activity in the hypothalamus may be regulated by glutamatergic signaling [22]. Similarly, VP signaling may also modulate dopaminergic activity as illustrated by an increase in dopamine type 2 receptors in the striatum of VP deficient rats [27][28][29]. Collectively, the interactive relationship between VP and the dopamine and glutamate systems provide a rationale to consider agents that alter VP activity as potential candidates for pharmacological interventions in schizophrenia.…”