Amphetamine‐induced Hyperlocomotor Activity in Heterozygous Disc1 Mutant Mice

Abstract

Disrupted‐in‐Schizophrenia‐1 (DISC1) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, various Disc1 mutant mouse models were established. In our group, Disc1 mutant mice were generated by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into the C57BL/6J strain. In this study, a battery of behavioral tests was conducted to evaluate the behavioral phenotypes and cognitive function in the heterozygous Disc1 mutant (Het) mice. In open field test, novel object recognition test, Y‐maze test, and prepulse inhibition test, no significant differences were observed between wildtype (WT) and Het mice. However, after receiving an intraperitoneal injection of amphetamine (5 mg/kg), greater locomotor activity was noticed in Het mice comparing with WT. Moreover, the results of western blot showed lower levels of dopamine transporter (DAT), D1 dopamine receptor (DRD1) and Glycogen synthase kinase 3 (GSK3α/β) and higher level of D2 dopamine receptor (DRD2) in the striatum of Het mice, relative to the WT mice. The dendritic structures of striatal medium spiny neurons were also examined. In the Het mice, reduced dendritic complexity and spine density were noticed. Our results indicated that Disc1 deficit in one allele dose does not alter the basic behavior and cognitive performance in mice. However, lacking one WT Disc1 allele causes the animals to be more vulnerable to the challenge of psychostimulant such as amphetamine, which might be attributed by the altered structure and functions of striatal cells.