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In addition to plasma membrane sites
In addition to plasma membrane sites, OCT3 was also observed associated with endomembranes, including mitochondrial membranes, with particularly strong expression in the outer nuclear membranes of both neurons and astrocytes (Gasser et al., 2017), indicating that, in addition to regulating extracellular monoamine levels, OCT3 may also determine the intracellular localization and/or actions of monoamines. Specifically, intracellular OCT3 may gate access of monoamines to metabolizing enzymes, including monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), which have been identified in the nuclear envelope (Muller and Da, 1977; Myohanen and Mannisto, 2010; Ulmanen et al., 1997) as well as in mitochondria. Another potential role for nuclear expression of OCT3 is suggested by recent studies demonstrating that adrenergic receptors can be found localized to inner nuclear membranes in cardiomyocytes, and that norepinephrine-induced activation of these receptors is mediated by OCT3 (Dahl et al., 2015; Vaniotis et al., 2013; Wu et al., 2014; Wu and O'Connell, 2015). A similar role for OCT3 was recently demonstrated by Irranejad et al. (2017). In these studies, OCT3-mediated transport was required for activation of beta-adrenoceptors localized to the Golgi endomembranes.
Interactions between stress, glucocorticoids, and norepinephrine/epinephrine: the role of OCT3
Although early studies confirmed the presence of uptake2 of norepinephrine and normetanephrine in hypothalamic and striatal slices, demonstrating that this uptake system was present in the Ponesimod (Hendley et al., 1970; Shaskan and Snyder, 1970), most studies that have examined corticosteroid-sensitive norepinephrine transport have been conducted in vascular smooth muscle. These studies have clearly demonstrated that corticosteroids rapidly increase extracellular norepinephrine concentrations, potentiating physiological responses to norepinephrine in a GR- and transcription-independent fashion (Horvath et al., 2003). The only study to examine a role for OCT3 in regulating extracellular norepinephrine concentrations used microdialysis to show that normetanephrine, a competitive inhibitor of OCT3, potentiated the effects of low-dose venlafaxine on extracellular norepinephrine levels in the hippocampus (Rahman et al., 2008). In this study, normetanephrine also potentiated desipramine-induced decreases in immobility in the tail suspension test. Corticosteroid-induced inhibition of OCT3 would be expected to act in a similar fashion, though this has not been directly examined. This mechanism may in part underlie the ability of corticosterone to enhance the effects of electric footshock on extracellular norepinephrine concentrations in the basolateral amygdala and consolidation of memory for inhibitory avoidance (McReynolds et al., 2010). In these studies, corticosterone pre-treatment potentiated subthreshold footshock-induced increases in norepinephrine levels within the basolateral amygdala (BLA) and enhanced inhibitory avoidance memory.
Interactions between stress, glucocorticoids, and dopamine: the role of OCT3
Stress and glucocorticoids have been reported to acutely increase extracellular DA concentrations, particularly in the striatum, and these effects have been linked to the influence of stress on the abuse of cocaine and other drugs. Electric footshock increased extracellular DA in the shell, but not the core, of the nucleus accumbens (Kalivas and Duffy, 1995). The role of glucocorticoids in stress-induced increases in extracellular DA is supported by studies in which intravenous infusion of corticosterone resulted in significant increases in striatal DA concentrations measured by microdialysis. Interestingly, these effects of corticosterone were observed when the infusion occurred in the dark period (when DA neurons are most active), but not when the infusion occurred during the light period. A similar effect was observed when corticosterone was administered in the drinking water. Corticosterone ingestion during the dark phase, but not during the light, led to increases in extracellular DA in the striatum (Piazza et al., 1996). The timing of glucocorticoid-induced increases in DA in these studies is not clear as the temporal resolution of microdialysis is limited. Greater temporal resolution is provided by electrochemical studies. Mittleman and colleagues used chronoamperometry to compare the acute effects of corticosterone administration on nucleus accumbens DA to those of acute amphetamine. Both treatments led to significant and comparable increases in extracellular DA. Interestingly, while the amphetamine-induced increase in extracellular DA was observed within seconds of injection, the effect of corticosterone was delayed, with a latency of 16–18 min (Mittleman et al., 1992). This differential timing is consistent with the proposed mechanisms of action of the two treatments, with amphetamine inducing DA release via reverse transport, and corticosterone potentially reducing clearance of tonically released DA. In one of the first studies to provide evidence for glucocorticoid-sensitive DA clearance in the central nervous system, Gilad et al. demonstrated that the synthetic glucocorticoid methylprednisolone decreased DA uptake by septal synaptosomes within 10 min of application (Gilad et al., 1987).