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 D₂ 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 D₂-related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia.