title: (+/-) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics.
abstract: 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.
authors.affiliation: Psychiatry CEDD, GlaxoSmithKline, Third Avenue, Harlow, UK. Jackie.2.Cilia@gsk.com
authors.forename: Jackie
authors.initials: J
authors.lastname: Cilia
authors.forename: Paula
authors.initials: P
authors.lastname: Hatcher
authors.forename: Charlie
authors.initials: C
authors.lastname: Reavill
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000077213:Lamotrigine; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D013449:Sulfonamides; D013876:Thiophenes; D014227:Triazines; D018698:Glutamic Acid; D007649:Ketamine; C121465:6-methyl-2-(phenylethynyl)pyridine; D003024:Clozapine; D006220:Haloperidol; C117443:SB 271046; D018967:Risperidone; D000077213:Lamotrigine