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Journal of Psychopharmacology, Vol. 21, No. 3, 302-311 (2007)
DOI: 10.1177/0269881107077718

(±) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics

Jackie Cilia

Psychiatry CEDD, GlaxoSmithKline, Harlow, UK, Jackie.2.Cilia{at}gsk.com

Paula Hatcher

Psychiatry CEDD, GlaxoSmithKline, Harlow, UK

Charlie Reavill

Psychiatry CEDD, GlaxoSmithKline, Harlow, UK

Declan N. C. Jones

Psychiatry CEDD, GlaxoSmithKline, Harlow, UK

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (the prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in psychiatric disorders such as schizophrenia. Ketamine, a non-competitive N-methyl-D-aspartate antagonist has been shown to induce schizophrenia-Like behavioural changes in humans and PPI deficits in rats, which can be reversed by antipsychotics. Thus, ketamine-induced PPI deficits in rats may provide a translational model of schizophrenia. The aim of this study was to investigate the effects of antipsychotic drugs and drugs known to alter the glutamate system upon ketamine-induced PPI deficits in rats. Rats were habituated to the PPI procedure [randomized trials of either pulse alone (110 dB/50 ms) or prepulse + pulse (80 dB/10 ms)]. Animals were assigned to pre-treatments based on the level of PPI on the last habituation test and balanced across startle chambers. Ketamine (1—10 mg/kg s.c; 15 min ptt) increased startle ampLitude and induced PPI deficits at 6 and 10 mg/kg. PPI deficits induced by ketamine at 6 mg/kg were not attenuated by clozapine (2.5—10 mg/kg s.c.; 60 min ptt), risperidone (0.1—1 mg/kg i.p.; 60 min ptt), haloperidoL (0.1—1 mg/kg i.p.; 60 min ptt), lamotrigine (3—30 mg/kg p.o.; 60 min ptt), or SB-271046-A (5—20 mg/kg p.o.; 2 hour ptt) nor potentiated by 2-methyl-6-(phenylethynyl)-pyridine (3—10 mg/kg i.p.; 30 min ptt). These results suggest that under these test conditions ketamine-induced PPI deficits in rats is relatively insensitive and does not represent a translational model for drug discovery in schizophrenia.

Key Words: ketamine • prepulse inhibition • rat • clozapine • risperidone • haloperidol • Lamotrigine • MPEP • SB-271046-A • schizophrenia


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