An organic cation transporter capable of transporting serotonin is upregulated in serotonin transporter-deficient mice

The serotonin (5HT) transporter (5HTT) regulates serotonergic neurotransmission by mediating the reuptake of 5HT from the synaptic cleft. The organic cation transporter (OCT) gene family physiologically transports a wide spectrum of organic cations. Although lacking the high affinity and selectivity of the 5HTT, OCT1 and OCT3 mediate low-affinity 5HT transport and therefore may participate in the clearance of excessive 5HT. Since concentrations of extracellular 5HT are increased in the brain of 5HTT-deficient mice, we investigated the role of OCTs in 5HT system homeostasis. We analyzed OCT1 and OCT3 gene expression in the brain of 5HTT knockout mice by semi-quantitative competitive PCR and in situ hybridization. We demonstrate that in 5HTT-deficient mice OCT3 mRNA concentrations were significantly increased in the hippocampus. In contrast, OCT1 expression was unchanged. Upregulation of OCT3 expression and enhanced low-affinity 5HT uptake may limit the adverse effects of elevated extracellular 5HT and may play a critical role in maintaining 5HT-dependent functions of the hippocampus in the absence of 5HTT.