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Considerable information about the physiologic role of OCT3 has been obtained in various elegant studies in Oct3 knockout mice. As with Oct1 and Oct2 knockout mice, Oct3 ^−/− mouse are viable, fertile, have a normal lifespan, and show no obvious physiological defect. In mice, deletion of Oct3 results in substantially reduced levels of MPP⁺ in the heart, embryo, and salivary glands. However, no significant differences in the endogenous levels of two OCT3 substrates, norepinephrine and dopamine, were observed in the embryo or placenta of wild‐type versus Oct3 ^−/− mice [46].

Though OCT3 is expressed in the liver, no obvious liver phenotype has been observed between Oct3 ^−/− and wild‐type mice on normal chow. However, after induction by diethylnitrosamine and phenobarbital [47], Oct3 ^−/− mice exhibit increased tumorigenesis in the liver, suggesting the transporter may play a role in hepatocellular carcinoma.

As an excellent transporter for histamine, OCT3 appears to play a role in determining histamine levels and associated immunologic phenotypes. For example, a significant increase in histamine content in the spleen has been observed in Oct3 ^−/− mice compared with wild‐type mice. Consistent with these observations, in an endotoxemia model involving LPS injection (20 mg/kg) into the peritoneal cavity, Oct3 ^−/− mice exhibit a significant decrease in survival rate compared with wild‐type mice. These studies suggest that OCT3 plays a role in immunological response in endotoxemia through its role as a histamine transporter.

Because of its expression in the central nervous system, OCT3 has been investigated for effects on behavior, particularly regarding locomotion and anxiety. Oct3 ^−/− mice have a decreased dopamine concentration in several brain regions (i.e., substantia nigra, tegmental area) [48]. Several behavioral tests reveal higher scores for anxiety compared with wild‐type mice [49]. Further high doses of amphetamine or cocaine increase locomotor activity in Oct3 ^−/− mice, but not in wild‐type mice. The mechanism for its effects on behavior may be that the transporter takes up biologically active amines and without it, the amines are present at higher levels, causing effects on locomotion and other CNS phenotypes.

With respect to the exogenous drug metformin, Oct3 ^−/− mice exhibit substantial decreases in oral bioavailability compared with wild‐type mice. Tissue‐to‐plasma ratios are significantly lower in the liver, kidney, adipose tissue, and skeletal muscle in Oct3 ^−/− mice, suggesting OCT3 plays an important role in tissue distribution of metformin [2]. However, blood glucose levels in Oct3 ^−/− mice do not significantly change after metformin administration, indicating the altered pharmacokinetic profiles may not translate into an effect on pharmacodynamic response.