Neurotensin-Deficient Mice Have Deficits in Prepulse Inhibition: Restoration by Clozapine but Not Haloperidol, Olanzapine, or Quetiapine

Abstract

Prepulse inhibition (PPI) of the acoustic startle reflex is a commonly used measure of preattentive sensorimotor gating. Disrupted PPI in rodents represents an animal model of the sensorimotor gating deficits characteristic of schizophrenia. The neurotensin (NT) system is implicated in the pathophysiology of schizophrenia, and NT has been hypothesized to act as an endogenous antipsychotic. In rats, NT receptor agonists restore PPI disrupted by dopamine receptor agonists and Nmethyl-D-aspartate receptor antagonists, and pretreatment with an NT receptor antagonist blocks restoration of isolation rearing induced deficits in PPI by some antipsychotic drugs. The current studies further scrutinized the role of the NT system in the regulation of PPI and in antipsychotic drug-induced restoration of PPI using NT-null mutant mice (NT Ϫ/Ϫ ). NT Ϫ/Ϫ mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared with NT ϩ/ϩ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 min before PPI testing significantly increased PPI in NT ϩ/ϩ mice but had no effect on PPI in NT Ϫ/Ϫ mice. In contrast, clozapine (1.0 mg/kg) significantly increased PPI in both NT Ϫ/Ϫ and NT ϩ/ϩ mice, whereas olanzapine (0.5 mg/kg) had no effect on PPI in either NT Ϫ/Ϫ or NT ϩ/ϩ mice. In a separate experiment, amphetamine (2.0 mg/kg i.p.) significantly disrupted PPI in NT ϩ/ϩ mice but not NT Ϫ/Ϫ mice. These results provide evidence that the effects of antipsychotic drugs (APDs) may be differentially affected by the state of NT neurotransmission and, moreover, that APDs differ in their dependence on an intact NT system.

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

“…The increased PPI in the wild type mice after administration of antipsychotics in the present study is in accord with other studies demonstrating effects of antipsychotics on PPI in different mouse strains (Kinkead et al 2005;Lipina et al 2005;Olivier et al 2001;Ouagazzal et al 2001).…”

Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L

“…Our results indicate that NTS1 is necessary for normal disruption of PPI by the indirect DA agonist d-amphetamine and the non-competitive NMDA receptor antagonist dizocilpine. Our results are consistent with previous reports on the important role of NTS1 in the modulations of PPI, as found by pharmacological interventions (Caceda et al, 2005;Kinkead et al, 2005). Analysis of startle pulse alone ASR data showed a significant decrease in startle magnitude with amphetamine alone disruption for WT mice, a trend often reported in other studies that have used amphetamine to disrupt PPI (Dulawa and Geyer, 1996;Feifel et al, 2010b;RalphWilliams et al, 2002;Ralph et al, 2001;Ralph et al, 1999;Varty et al, 2001).…”

“…There is significant evidence implicating NTS1 in the sensorimotor gating mechanism of PPI (Binder et al, 2001;Caceda et al, 2005;Feifel et al, 2007;Feifel et al, 2004;Kinkead et al, 2005). Our results indicate that NTS1 is necessary for normal disruption of PPI by the indirect DA agonist d-amphetamine and the non-competitive NMDA receptor antagonist dizocilpine.…”

Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis

“…1 D and E). When wild-type and NT KO mice (15,16) were examined after exposure to intracolonic TNBS for 2 days, TNBS-exposed wild-type mice had increased colitis clinical scores, as defined by the criteria listed in our previous report (17), with substantial weight loss compared with vehicle-exposed littermates ( Fig. 2 A and B).…”