Regulation of cocaine-reinstated drug-seeking behavior by κ-opioid receptors in the ventral tegmental area of rats

Abstract

Rationale-Relapse is one of the main challenges facing the current treatment of cocaine addiction. Understanding its neurobiological mechanism is a critical step toward developing effective antirelapse therapies.Objectives-Emerging evidence indicates that glutamate-mediated activation of dopamine (DA) neurons in the ventral tegmental area (VTA) may be critically involved in cocaine-induced relapse to drug-seeking behavior. Activity of VTA DA neurons is modulated by multiple neurotransmitter systems including opioids, serotonin, dopamine, and acetylcholine. Recent studies demonstrated that activation of κ-opioid receptors (κORs) in the rat VTA directly inhibits the activity of a subpopulation of DA neurons projecting to the prefrontal cortex (PFC) and amygdala. Because we previously showed that blockade of DA receptors in the dorsal PFC inhibits cocaine-induced reinstatement of extinguished cocaine-seeking behavior suggesting a critical role of the VTA-PFC DA circuit in this process, we tested the hypothesis that activation of κORs in the VTA will block cocaine-induced reinstatement in rats.Methods-Rats were trained to self-administer intravenous cocaine (0.125 mg/infusion) under a modified fixed-ratio five schedule. After extinction of the learned behavior, the effects of activation of VTA κORs on cocaine-induced reinstatement were studied.Results-The κOR agonist U50 488 (0-5.6 μg/side) microinjected into the VTA dose-dependently decreased cocaine-induced reinstatement. The effects could not be explained by either a disruption of operant behavior or diffusion of the drug to the areas surrounding the VTA. Moreover, the effect was reversed by norbinaltorphimine.Conclusions-The VTA DA neurons expressing functional κORs are critically involved in cocaine-induced reinstatement in rats.

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…Thus subtle differences in drug action between cocaine (monoamine transporter blocker) versus amphetamine (monoamine transporter reverser) may explain why KOR agonists are more effective in attenuating cocaine-induced reinstatement. Intra-VTA microinjection of U50,488 decreases cocaine-primed cocaine reinstatement in a dose-dependent manner, and this effect was blocked by intra-VTA nor-BNI microinjection [332]. Intra-VTA U50,488 was without effect on cocaine and food responding after acquisition as well as on food-induced reinstatement of food selfadministration.…”

“…However, systemic administration of KOR agonists at doses that did not alter responding for natural reinforcers was also shown to decrease cocaine self-administration [328,331], and this may be ligand-specific [331]. Intra-VTA U50,488 microinjection does not alter responses for cocaine maintained under a FR5 schedule [332], suggesting that maintenance of cocaine self-administration is not modulated by VTA KORs. Systemic nor-BNI administration does not alter cocaine self-administration in rats under an FR1 schedule [328,333].…”

Kappa Opioid Receptor-Mediated Disruption of Novel Object Recognition: Relevance for Psychostimulant Treatment

“…In support, KOR agonists inhibit presynaptic glutamate release and post-synaptic NMDAR potentials [53,75–77] and infusion of KOR agonists to the VTA inhibit midbrain dopaminergic cells [78,79]. Moreover, intra-VTA KOR activation influences psychostimulant effects, decreasing sensitization to cocaine seeking [80] and attenuating cocaine-induced repetitive motor behavior [81]. Recently, cocaine-reinstatement was found to be dampened among squirrel monkeys administered a KOR agonist in a nor-BNI-dependent manner [82].…”

A single injection of a novel kappa opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats

“…Kappa opioid receptor (KOPr) agonists have previously been shown to antagonize several cocaine-induced behaviors such as self-administration (Glick et al , 1995; Kuzmin et al , 1997), reinstatement of drug-seeking (Schenk et al , 1999; 2000, Morani et al , 2009; Sun et al , 2010), hyperactivity (Heidbreder et al , 1993; Vanderschuren et al , 2000; Collins et al , 2001) and sensitization to conditioned rewarding effects (Shippenberg et al , 1996; Heidbreder et al, 1995). These potential anti-addictive properties of this class of compounds have prompted studies aimed at developing KOPr ligands as anti-addiction pharmacotherapies (Mello and Negus, 2000; Prisinzano et al , 2005; Shippenberg et al , 2007; Tomasiewcz et al , 2008).…”