Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking

Abstract

Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intraaccumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake 2 -mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake 2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake 2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake.

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

“…Corticosterone-induced inhibition of OCT3-mediated transport is GR-independent, non-genomic, and likely involves direct binding to OCT3 (Gründemann et al, 1999;Horvath et al, 2003;Gorboulev et al, 2005). Moreover, it appears to elevate monoamine levels in vivo (Gasser et al, 2006;Baganz et al, 2010;Graf et al, 2013), posing it as a potential GR-independent mechanism through which glucocorticoids regulate behavior. However, to date, there is no direct evidence that glucocorticoids exert actions on behavior via inhibition of OCT3.…”

“…A consequence of such alterations appears to be a heightened susceptibility to drug-seeking behavior. We recently established a rat self-administration/reinstatement model in which acute stress potentiates the reinstatement of cocaine seeking in response to an otherwise subthreshold priming dose of cocaine but does not by itself directly evoke cocaine seeking (Graf et al, 2013;McReynolds et al, 2016). This stage-setting effect of stress appears to be mediated by glucocorticoids, in that the ability of footshock to potentiate reinstatement in response to a subthreshold low dose of cocaine is eliminated by adrenalectomy, and mimicked in the absence of stress by administration of corticosterone at a dose that results in plasma levels comparable to those observed during stress.…”

“…This stage-setting effect of stress appears to be mediated by glucocorticoids, in that the ability of footshock to potentiate reinstatement in response to a subthreshold low dose of cocaine is eliminated by adrenalectomy, and mimicked in the absence of stress by administration of corticosterone at a dose that results in plasma levels comparable to those observed during stress. The effect also appears to be mediated by a GR-independent mechanism, as it is insensitive to pretreatment with the GR antagonist RU38486 (Graf et al, 2013). A role for inhibition of OCT3 in these actions of corticosterone is suggested by the fact that corticosterone potentiates low-dose cocaine-induced increases in nucleus accumbens (NAc) dopamine, that corticosterone treatment decreases dopamine clearance in the NAc via a DATindependent mechanism, and that corticosterone-induced potentiation of reinstatement is mimicked by treatment with normetanephrine, a non-glucocorticoid blocker of OCT3-mediated transport (Graf et al, 2013).…”

“…The effect also appears to be mediated by a GR-independent mechanism, as it is insensitive to pretreatment with the GR antagonist RU38486 (Graf et al, 2013). A role for inhibition of OCT3 in these actions of corticosterone is suggested by the fact that corticosterone potentiates low-dose cocaine-induced increases in nucleus accumbens (NAc) dopamine, that corticosterone treatment decreases dopamine clearance in the NAc via a DATindependent mechanism, and that corticosterone-induced potentiation of reinstatement is mimicked by treatment with normetanephrine, a non-glucocorticoid blocker of OCT3-mediated transport (Graf et al, 2013).…”

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics

“…In fact, corticosterone facilitates the acquisition of cocaine self-administration in rats (Mantsch et al, 1998) and potentiates the reinstatement of cocaine-seeking (Graf et al, 2013).…”