To confirm a role of OCT in corticosterone induced

To confirm a role of OCT3 in corticosterone-induced potentiation of cocaine-primed reinstatement, we examined the interaction of corticosterone and cocaine in the reinstatement of cocaine conditioned place preference (CPP) in wild type mice, and transgenic OCT3-deficient mice. These mice express a truncated form of OCT3, and lack OCT3-mediated transport activity (Zwart et al., 2001). Systemic administration of either corticosterone or normetanephrine potentiated reinstatement of CPP in response to a previously subthreshold dose of cocaine in wild type mice but had no effect in OCT3-deficient mice (McReynolds et al., 2017). An intriguing distribution of OCT3 in the greater amygdaloid complex suggests a potential role for OCT3 in stress-dependent dopaminergic regulation of amygdala output. Hill and Gasser demonstrated that OCT3 expression was highly enriched in the intercalated cell (ITC) groups of the amygdala (Hill and Gasser, 2013). These groups consist primarily of striatal-like, γ-aminobutyric prostaglandin e2 (GABA)ergic neurons that project to the basolateral amygdaloid complex, and potently regulate neurotransmission and plasticity involved in the consolidation of fear memory (Pare et al., 2004). The ITCs are densely innervated by dopaminergic projections from the ventral tegmental area (VTA), and densely express D1 receptors (Marowsky et al., 2005). Dopamine, acting through D1 receptors, inhibits ITC GABAergic neurons, resulting in disinhibition of the BLA and central nucleus of the amygdala (CeA) (Marowsky et al., 2005). The dense expression of both OCT3 and D1 receptors on ITC GABAergic neurons suggests that, under baseline conditions, DA levels are kept low via high activity of OCT3. During stress, corticosterone, by inhibiting OCT3-mediated clearance, would be expected to lead to increases in extracellular DA concentrations, which would, by activating local D1 receptors, inhibit ITC activity, thus, disinhibiting amygdala output.
Interactions between stress, glucocorticoids, and serotonin: the role of OCT3 Studies in T. granulosa showing that corticosterone induced rapid increases in tissue concentrations of 5-HT within the DMH led us to explore the effects of local inhibition of OCTs on extracellular 5-HT concentrations within the rat DMH. Infusion of the OCT blocker, decynium 22, via the microdialysis probe, into the DMH, dose dependently increased 5-HT concentrations in the DHM (Feng et al., 2005). In a subsequent study, we demonstrated that similar responses were observed following local administration of corticosterone into the rat DMH, but this effect was context dependent (i.e., observed in rats with peripheral administration of the 5-HT-releasing drug, fenfluramine, but not in vehicle-treated controls), an effect consistent with the hypothesis that corticosterone inhibits 5-HT clearance in the DMH (Feng et al., 2009). Finally, we demonstrated that increases in extracellular 5-HT following administration of decynium 22 were exaggerated in rats exposed to restraint stress, relative to vehicle-treated controls (Feng et al., 2010). A role for OCT3 in these effects in the DMH was supported by demonstration that ex vivo histamine accumulation in DMH tissue could be inhibited by 5-HT, corticosterone, decynium 22, and estradiol, consistent with OCT3 pharmacology (Gasser et al., 2006). Although the physiological and behavioral consequences of OCT3/5-HT interactions in the DMH are not known, they may play a role in negative feedback regulation of the HPA axis (Stamper et al., 2017; Stamper et al., 2015). Elegant studies by Lynnette Daws and colleagues, using high speed chronoamperometry, demonstrated a low affinity, high capacity 5-HT clearance mechanism in the rat hippocampus after pharmacological blockade of the sodium-dependent, high-affinity, low-capacity 5-HT transporter SERT (Daws et al., 2005). Subsequently, the same group demonstrated that in mice lacking SERT, the same 5-HT clearance mechanism was evident and was blocked by local application of decynium 22 or corticosterone (Baganz et al., 2008), suggesting a role for OCT3 in 5-HT reuptake in hippocampus. The relative contribution of OCT3, relative to SERT or other transporters, to 5-HT clearance under baseline or stress conditions is not known and will require further study. Consistent with the hypothesis that OCT3 inhibition is involved in stress-induced alterations in serotonin clearance, further studies in the Daws laboratory demonstrated that OCT3 expression and function were decreased in the hippocampi of mice exposed to repeated swim stress (Baganz et al., 2010).