The organic cation transporter (OCT) 3 is widely expressed in various organs in 
humans, and involved in the disposition of many exogenous and endogenous 
compounds. Several lines of evidence have suggested that OCT3 expressed in the 
brain plays an important role in the regulation of neurotransmission. Relative 
to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered 
behavioral and neurochemical responses to psychostimulants such as amphetamine 
(AMPH) and methamphetamine. In the present study, both in vitro and in vivo 
approaches were utilized to explore potential mechanisms underlying the 
disparate neuropharmacological effects observed following AMPH exposure in Oct3 
KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated 
that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was 
determined to be a high-capacity and low-affinity transporter for the 
neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). 
Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory 
effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 
substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) 
values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting 
DA and 5-HT uptake, respectively, while 50% inhibition of NE and 
4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by 
even the highest concentration of d-AMPH applied (100 microM). Furthermore, the 
disposition of d-AMPH in various tissues including the brain, liver, heart, 
kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in 
both male and female Oct3 KO and WT mice. No significant difference was observed 
between either genotypes or sex in all tested organs and tissues. Our findings 
suggest that OCT3 is not a prominent factor influencing the disposition of 
d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, 
d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the 
brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 
KO and WT mice appear to be due to the absence of Oct3 mediated uptake of 
neurotransmitters in the KO mice.