- Objective: Lithium (Li), the drug of choice in bipolar disorder, reduces the function of the sodium-myo-inositol cotransporter 1 (SMIT1) and was shown to decrease brain myo-inositol levels in rodents. Reduction in brain myo-inositol was also found in SMIT1 knockout mice (Agam et al.2009). Homozygous but not heterozygous SMIT1 knockout mice were shown to exhibit lithium-like behavior in the pilocarpine-induced seizure paradigm and the forced swimming test (Agam et al. 2009). In rodents, chronic Li treatment results in reduced amphetamine-induced hyperactivity (Gould et al. 2006). Methods: SMIT1 homozygous knockout male mice, 2.5-4.5 month old (n=19) and their wildtype littermates (n=26) were placed individually in the center of an activity monitoring box for 60 min while their behavior digitally recorded. The mice were then injected intraperitoneally with 2.5 mg/kg d-amphetamine and placed back each in its original monitoring box for additional 110 min during which locomotion (footage) was digitally recorded using a video tracking system (Ethovision). Results: No difference in locomotion was found between the groups before amphetamine injection. SMIT1 homozygous knockout mice exhibited significantly less locomotion than their littermate wildtypes during the first hour following amphetamine injection (two way repeated measures ANOVA, timeXgenotype, F(5,215)=3.7, p=0.003) and remained less active during the second hour after amphetamine injection (repeated measures ANOVA, group effect, F(1,43)=6.8, p<0.01). Conclusions: Our results show that SMIT1 KO mice exhibit lithium-like effect on amphetamine- induced hyperactivity. Together with the findings in the lithium-pilocarpine paradigm and the forced swimming test, these results support the involvement of myo-inositol in the mood stabilizing effect of Li.