Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia.
Significant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal D receptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D(2) receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D(2) -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia.
Lipina
T V
TV
Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, Canada. lipina@lunenfeld.ca
Niwa
M
M
Jaaro-Peled
H
H
Fletcher
P J
PJ
Seeman
P
P
Sawa
A
A
Roder
J C
JC
D000161:Acoustic Stimulation; D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000235:genetics / Q000502:physiology
D015306:Biogenic Monoamines; C498794:Disc1 protein, mouse; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D006220:Haloperidol; D004298:Dopamine