Further neurochemical and behavioural investigation of Brattleboro rats as a putative model of schizophrenia.
Brattleboro (BRAT) rats are a mutant variant of the Long-Evans (LE) strain deficient in the neurohormone vasopressin. BRAT rats show behavioural alterations relevant to schizophrenia. In particular, BRAT rats show deficits in prepulse inhibition (PPI) and alterations in various measures of cognition. The aim of this study was to replicate the reported PPI deficits in BRAT rats and its reversal by antipsychotic drugs and to investigate other behavioural and neurochemical characteristics. Acoustic startle reactivity, PPI, spontaneous and amphetamine-induced locomotor activity (LMA) and ex-vivo steady state neurochemistry were measured in male homozygous BRAT rats and LE rats. The effects of antipsychotics on PPI deficits were also determined. Relative to LE, BRAT rats showed enhanced startle reactivity, hyperactivity to a novel environment, PPI deficits and decreased levels of dopamine and DOPAC (dihydroxyphenylacetic acid) in the frontal cortex. BRAT and LE rats showed similar levels of hyperactivity following amphetamine (0.26 mg/kg s.c.). PPI deficits were attenuated by acute clozapine (5-10 mg/kg s.c.), risperidone (0.1-1 mg/kg i.p.), haloperidol (0.1-0.5 mg/kg p.o.) and less robustly by olanzapine (0.3-3 mg/kg s.c.). Chronic administration of clozapine (5 mg/kg s.c., once daily) attenuated baseline hyperactivity and elevated PPI of both strains. Clozapine concentrations were higher in BRAT brains compared with LE rats. These data confirm the reported PPI deficit in BRAT rats and its reversal by antipsychotic drugs, suggesting BRAT rats may represent a potential model for identifying novel antipsychotic drugs.
Cilia
J
J
Department of Biology, New Frontiers Science Park, GlaxoSmithKline plc, Harlow, Essex, UK.
Gartlon
J E
JE
Shilliam
C
C
Dawson
L A
LA
Moore
S H
SH
Jones
D N C
DN
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011910:Rats, Brattleboro / Q000378:metabolism*; D020318:Rats, Long-Evans; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
D014150:Antipsychotic Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D004298:Dopamine