Received for publication April 4, 2005.
Revised June 24, 2005.
Accepted for publication June 24, 2005.

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 NMDA receptor antagonists, and pretreatment with a 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 utilizing NT-null mutant mice (NT^-/-). NT^-/- mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared to NT^+/+ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 minutes before PPI testing significantly increased PPI in NT^+/+ mice but had no effect on PPI in NT^-/- mice. In contrast, clozapine (1.0 mg/kg) significantly increased PPI in both NT^-/- and NT^+/+ mice whereas olanzapine (0.5 mg/kg) had no effect on PPI in either NT^-/- or NT^+/+ mice. In a separate experiment, amphetamine (2.0 mg/kg, i.p.) significantly disrupted PPI in NT^+/+ mice but not NT^-/- mice. These results provide evidence that the effects of APDs may be differentially affected by the state of NT neurotransmission and moreover that APDs differ in their dependence on an intact NT system.

Key words: Knock out, acoustic startle, amphetamine, antipsychotic drug, peptide, sensorimotor gating