Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn

Abstract

Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappaopioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaineexposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappaopioid receptor antagonists may be useful therapeutics for cocaine abuse.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…The findings of the present study are consistent with previous reports (Beardsley et al 2005;Carey et al 2007;Valdez et al 2007). Beardsley et al (2005) showed that intermittent and uncontrollable footshock was able to reinstate active lever responding on a lever previously associated with cocaine self-administration and that pre-treatment with the kappa antagonist JDTic attenuated footshock-induced cocaine-seeking behavior.…”

“…In contrast, both the footshock and forced swim were administered in a different apparatus and room in the reinstatement protocol described in the present study. This is consistent with recent reports from other research groups also showing that stress exposure outside the experimental chamber was able to reinstate drug seeking (Carey et al 2007;Kreibich andBlendy 2004, Ribeiro Do Cotuo et al 2006). Differences between reinstatement results obtained using operant self-administration protocols and place-conditioning protocols likely reflect the differences in the underlying learning mechanisms.…”

“…Consistent with this prediction, rodents given either an intermittent footshock or a forced swim stressor failed to reinstate drug-seeking behaviors after administration of kappa receptor antagonists (Beardsley et al 2005;Carey et al 2007). In this study, we extend these findings by determining the effects of the kappa antagonist norbinaltorphimine and disruption of the kappa system by gene deletion of either the kappa opioid receptor or the endogenous ligand dynorphin on forced-swim-stress-and foot-shockstress-induced reinstatement of cocaine-conditioned place preference.…”

“…Beardsley et al (2005) showed that intermittent and uncontrollable footshock was able to reinstate active lever responding on a lever previously associated with cocaine self-administration and that pre-treatment with the kappa antagonist JDTic attenuated footshock-induced cocaine-seeking behavior. Carey et al (2007) also demonstrated that the kappa receptor antagonist arodyn blocked forced-swim-stress-induced reinstatement of cocaine-seeking behavior using a conditioned place preference protocol. Beardsley et al (2005) and Carey et al (2007) also demonstrated that antagonism of the kappa receptor failed to attenuate cocaine-induced reinstatement.…”

“…Carey et al (2007) also demonstrated that the kappa receptor antagonist arodyn blocked forced-swim-stress-induced reinstatement of cocaine-seeking behavior using a conditioned place preference protocol. Beardsley et al (2005) and Carey et al (2007) also demonstrated that antagonism of the kappa receptor failed to attenuate cocaine-induced reinstatement.…”