Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: Potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission

Glucocorticoid hormones act within the brain to alter physiological and behavioral responses to stress-related stimuli. Previous studies indicated that acute stressors can increase serotonin [5-hydroxytryptamine (5-HT)] concentrations in the dorsomedial hypothalamus (DMH), a midline hypothalamic structure involved in the integration of physiological and behavioral responses to stress. The current study tests the hypothesis that rapid, stress-induced accumulation of 5-HT is attributable to the inhibition of 5-HT transport via organic cation transporters (OCTs). OCTs are a family of high-capacity, bidirectional, multispecific transporters of organic cations (including 5-HT, dopamine, and norepinephrine) only recently described in brain. In peripheral tissues, organic cation transport via some OCTs is inhibited by corticosterone. We examined the expression and function of OCTs in the periventricular medial hypothalamus of male Sprague Dawley rats using reverse-transcriptase (RT)-PCR, immunohistochemistry, and in vitro transport assays. RT-PCR revealed expression of OCT3 mRNA, but not OCT1 or OCT2 mRNA, in the medial hypothalamus. OCT3-like immunoreactivity was observed in ependymal and glial-like cells in the DMH. Acutely prepared minces of rat medial hypothalamic tissue accumulated the OCT substrates [ ³H]-histamine and [ ³H]-N-methyl-4- phenylpyridinium ([ ³H]-MPP⁺). Consistent with the pharmacological profile of OCT3, corticosterone, 5-HT, estradiol, and the OCT inhibitor decynium22 dose-dependently inhibited histamine accumulation. Corticosterone and decynium22 also inhibited efflux of [ ³H]-MPP ⁺ from hypothalamic minces. These data support the hypothesis that corticosterone-induced inhibition of OCT3 mediates stress-induced accumulation of 5-HT in the DMH and suggest that corticosterone may acutely modulate physiological and behavioral responses to stressors by altering serotonergic neurotransmission in this brain region.