Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior.

Contribution to Special Issue on Fast effects of steroids. Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by "uptake2" transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake2 processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed.