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. Kappa-opioid 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 cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.

Introduction

Despite the dangers and complications of cocaine abuse and addiction, cocaine remains an illicit drug of abuse with nearly 2 million American cocaine users (Johnston et al., 2006). Unfortunately, no Food and Drug Administration-approved medication is currently available for the treatment of cocaine abuse, even with our understanding of the neurobiological actions of cocaine. Cocaine is known to inhibit dopamine transporter activity, thus enhancing extracellular dopamine signaling (Heikkila et al., 1975). This cocaine-induced increase of synaptic dopamine levels in the A10 mesolimbic dopamine pathway is associated with the increased perception of cocaine's rewarding and addictive effects (Kuhar et al., 1991). From this, it is theorized that medications that suppress cocaine-induced increases in mesolimbic dopamine might prove to be effective treatments for cocaine abuse (Carroll et al., 1999).

Medications activating the kappa-opioid system reduce mesolimbic dopaminergic signaling (Spanagel et al., 1992), and may therefore prove useful in the treatment of cocaine abuse. However, the use of kappa-opioid receptor agonists can have therapeutic limitations. For example, while kappa-opioid receptor agonists given acutely are noted to suppress cocaine self-administration (Kreek, 1987), recent reports demonstrate that repeated administration paradoxically potentiates cocaine reward in a manner prevented by kappa-opioid receptor antagonists (Negus, 2004, McLaughlin et al., 2006). These data suggest that the long-term maintenance of cocaine-abstinent patients may be facilitated by preventing the activation of kappa-opioid receptors with receptor-specific antagonists. Supporting this, kappa-opioid receptor antagonists were shown to prevent stress-induced potentiation of the rewarding effects of cocaine (McLaughlin et al., 2003). Moreover, the kappa-opioid receptor antagonist (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was previously reported to suppress stress-induced reinstatement of cocaine self-administration, while cocaine-primed reinstatement of cocaine self-administration was unaffected (Beardsley et al., 2005). These findings suggest that kappa-opioid receptor antagonists may be valuable in the treatment of stress-induced relapse to drug-seeking behavior.

Arodyn, (Ac[Phe^1,2,3,Arg⁴,D-Ala⁸]dynorphin A-(1-11) amide) is a novel peptide ligand based on the structure of dynorphin A (Bennett et al., 2002, Bennett et al., 2005), an endogenous ligand for the kappa opioid receptor. Arodyn was previously characterized as a potent, highly selective kappa-opioid receptor antagonist (Bennett et al., 2002). As such, we hypothesized that arodyn pretreatment would prevent stress-induced reinstatement of cocaine-conditioned place preference.

This hypothesis was tested after first confirming the in vivo activity and duration of kappa-opioid receptor antagonism induced by arodyn. The antagonizing effect of a single administration of arodyn on kappa-opioid receptor agonist-induced antinociception was tested in C57Bl/6J mice using the 55 °C warm-water tail-withdrawal test. Once determined, the effect of arodyn pretreatment on mice exposed to stress or cocaine to induce reinstatement of cocaine-conditioned place preference was measured. Vehicle-pretreated mice demonstrated both stress- and cocaine-induced reinstatement of cocaine-conditioned place preference, whereas arodyn pretreatment prevented stress-, but not cocaine-induced, reinstatement. The results support the hypothesis that kappa-opioid receptor antagonists may prevent stress-induced reinstatement of cocaine reward, and suggest they may have therapeutic value in the treatment of relapse to psychostimulant abuse.