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  • The finding that OCT is expressed in the nucleus accumbens

    2023-05-26

    The finding that OCT3 is expressed in the nucleus accumbens (Gasser et al., 2009) suggests that inhibition of this transporter may underlie previously described effects of glucocorticoids on extracellular DA concentrations and indicates that DA clearance in this region is not mediated exclusively by the DA transporter (DAT). This poses an interesting mechanism by which glucocorticoids may interact with the effects of cocaine on dopaminergic neurotransmission, contributing to the effects of stress on drug-seeking behavior. Our group has provided evidence consistent with this mechanism by examining the interaction of subthreshold doses of cocaine with glucocorticoids in rodent models of addiction (Graf et al., 2013; McReynolds et al., 2017). In one set of studies (Graf et al., 2013), rats were trained to self-administer cocaine under short-access conditions (2 h daily access to the drug), followed by D-Mannitol training, in which lever presses no longer result in delivery of cocaine. These animals, as compared to those trained under long-access conditions, are relatively resistant to stress- or cocaine-induced reinstatement of drug seeking behavior. Specifically, neither injection of a low dose of cocaine (2.5 mg/kg), nor exposure to 15 min of intermittent electric footshock stress, led to significant reinstatement of drug-seeking behavior (lever presses despite the lack of cocaine delivery). However, the combination of these two stimuli (low dose cocaine preceded, 40 min earlier, by electric footshock) induced robust reinstatement (Graf et al., 2013). Similarly, intraperitoneal injection of corticosterone at a concentration that reproduces stress levels of the steroid, did not by itself lead to reinstatement, but potentiated low-dose cocaine-induced reinstatement, an effect that was not blocked by pretreatment with RU-38486, an inhibitor of the glucocorticoid receptor, but was blocked by intra-nucleus accumbens injection of fluphenazine, a DA receptor antagonist (Graf et al., 2013). Thus, corticosterone-induced potentiation appears to be mediated by a GR-independent, nongenomic mechanism involving local striatal DA signaling. The hypothesis that corticosterone-induced potentiation of reinstatement involves inhibition of OCT3-mediated clearance was supported by the demonstration that OCT3-like immunoreactivity was observed on both medium-spiny neurons and astrocytes in the nucleus accumbens, suggesting that OCT3 regulates extracellular DA concentrations by mediating postsynaptic and glial uptake, and that direct, intra-nucleus accumbens injection of either corticosterone or normetanephrine, a competitive inhibitor of OCT3, potentiated low-dose cocaine-induced reinstatement (Graf et al., 2013). We examined potential interactions of corticosterone and cocaine in the regulation of nucleus accumbens DA using microdialysis. These studies demonstrated that, while low-dose cocaine alone had no effect on extracellular DA concentrations in the nucleus accumbens, the same dose of cocaine induced significant increases in extracellular DA when it was preceded by systemic corticosterone injection (Graf et al., 2013). While these results are consistent with corticosterone inhibition of DA clearance, increases in DA measured by dialysis may be the result of increased release, decreased metabolism, or decreased clearance. To directly assess the effects of corticosterone on DA clearance, we used in vivo fast-scan cyclic voltammetry (FSCV), a technique that measures both release and clearance of DA on a millisecond time-scale. Corticosterone decreased the rate of DA clearance following electrically stimulated release in the nucleus accumbens of anesthetized animals after blockade of DAT. These studies revealed, for the first time, the presence of DAT-independent, corticosterone-sensitive DA clearance in vivo (Graf et al., 2013). In subsequent studies, we examined the effect of corticosterone on naturally-occurring DA transients in the nucleus accumbens of awake and behaving rats using FSCV. Systemic injection of low-dose cocaine alone had no effect on the amplitude or duration of accumbens DA transients, but robustly increased these measures when injected after systemic administration of corticosterone. Surprisingly, administration of corticosterone alone induced small but significant increases in both the magnitude and duration of these DA transients, demonstrating that corticosterone-induced decreases in DA clearance can be observed without blockade of the high-affinity clearance mechanism, and suggesting that the corticosterone-sensitive transporter contributes significantly to the shaping of dopamine signals in vivo (Wheeler et al., 2017).