Corticosterone-induced potentiation of cocaine seeking: A potential role for organic cation transporter 3

While it is known that stress plays a role in the relapse of cocaine-seeking behavior, recent studies demonstrate that stress may be acting as a "stage setter" rather than directly triggering further cocaine use. This model suggests stimuli that do not normally evoke relapse under stress-free conditions may result in drug seeking when the exposure occurs under stressful conditions. In this study, we examined the corticosterone-dependent potentiation of cocaine-induced reinstatement by a stressor, electric footshock (EFS), in rats following cocaine self-administration and extinction. We found that in rats with a history of drug exposure under low intake conditions, footshock alone did not reinstate cocaine seeking, but did result in a potentiation of reinstatement in response to a subthreshold dose of cocaine (2.5 mg/kg, ip.). This effect was abolished in adrenalectomized rats and reproduced in intact animals receiving a physiologically relevant dose of corticosterone (2.0 mg/kg, ip.). Administration of the glucocorticoid receptor (GR) antagonist RU-486 did not block these effects, suggesting a rapid, non-GR mediated mechanism. In order to determine the site of action, we performed in vivo microdialysis to measure dopamine levels in the nucleus accumbens (NAc) and found that, similar to its actions on cocaine-seeking behavior, corticosterone potentiated cocaine-induced increases in dopamine. In support of this evidence, direct administration of corticosterone into the NAc or prefrontal cortex (PFC) potentiated reinstatement to a subthreshold dose of cocaine, an effect that was blocked with pretreatment of the dopamine antagonist, fluphenazine. Through immunoflourescence studies, we have shown the presence of a high capacity, corticosterone sensitive, monoamine transporter, organic cation transporter 3 (OCT3), located in the NAc adjacent to tyrosine hydroxylase terminals, suggesting a potential interaction with dopamine clearance. Based on this, we hypothesize the mechanism involves corticosterone inhibition of OCT3-mediated dopamine clearance. In support of this mechanism, pretreatment of rats with normetanephrine, a non-glucocorticoid OCT3 inhibitor mimics the effect of corticosterone on reinstatement. These results suggest a novel mechanism through which stress may modulate dopaminergic signaling and promote drug-seeking behavior.