Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but not haloperidol, olanzapine, or quetiapine.
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 N-methyl-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-/-). NT-/- mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared with NT+/+ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 min 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 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.
Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Becky
B
Kinkead
Paul R
PR
Dobner
Vasili
V
Egnatashvili
Tiesha
T
Murray
Nancy
N
Deitemeyer
Charles B
CB
Nemeroff
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009496:Neurotensin / Q000502:physiology*; D000077152:Olanzapine; D000069348:Quetiapine Fumarate; D012018:Reflex / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D009496:Neurotensin; D000661:Amphetamine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine