Effects of the Kappa-opioid Receptor Agonist, U69593, on the Development of Sensitization and on the Maintenance of Cocaine Self-administration

Abstract

Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effects of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was alsoFollowing repeated exposure to cocaine and other stimulants, the behavioral and neurochemical responses to subsequent exposures increase. This sensitized response has been suggested to contribute to the development of compulsive drug-taking that characterizes abuse and to the maintenance of self-administration via the strengthening of stimulus/reward associations (Robinson and Berridge 1993;Shippenberg and Heidbreder 1995). If so, treatments that prevent or attenuate the development of sensitization might be effective adjuncts to the treatment of cocaine addiction.Preclinical studies have demonstrated the impor- NO . 4 tance of the mesocorticolimbic dopamine system in the maintenance of cocaine self-administration. For example, destruction of the ascending dopamine pathways via 6-hydroxydopamine (Roberts et al. 1977) or pretreatment with dopamine antagonists (Caine and Koob 1994;De Wit and Wise 1977) attenuated cocaine selfadministration and shifted the dose-effect curve for cocaine self-administration to the right (Caine and Koob 1994;Schenk et al. 1999). In addition, cocaine has been shown to be self-administered directly into the medial prefrontal cortex (Goeders and Smith 1983) the projection site of the mesocortical dopamine system.Recent studies have shown that dopamine release is modulated by manipulations of kappa-opioid receptor systems. For example, pretreatment with kappa-opioid receptor agonists inhibited basal DA release in the NAC (Devine et al. 1993;Shippenberg et al. 1994;Spanagel et al. 1992) whereas administration of a k-opioid receptor antagonist increased basal dopamine release (Spanagel et al. 1992). Manipulations of kappa-opioid receptor systems also affect many of the behavioral responses to cocaine. Pretreatment with kappa-opioid receptor agonists attenuated the discriminative stimulus properties (Riberdy et al. 1995; Bergman 1992, 1994), conditioned reinforcing effects (Crawford et al. 1995), and self-administration (Glick et al. 1995;Mello and Negus 1998;Negus et al. 1997;Schenk et al. 1999) of cocaine. Further, in an animal model of relapse, U69593 pretreatment attenuated the ability of an experimenter-delivered priming injection of cocaine to reinstate extinguished cocaine-taking behavior (Schenk et al. 1999).Kappa-opioid agonists also attenuate the sensitized responses that occur following repeated exposure to cocaine and other stimulants. When administered repeatedly with cocaine, the kappa-opioid agonists U50488 or U69593 prevented the cocaine-produced increase in the response of the mesolimbic dopamine system to subsequent cocaine exposures (Heidbreder et al. 1996(Heidbreder et al. , 1998 and attenuated the ability of cocaine preexposure to sensitize rats to the conditioned reinforcing and locomoto...

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

“…interactions in cocaine self-administration procedures Systemic U69,593 administration to rats produces a longlasting decrease in cocaine-seeking behavior in a paradigm in which a cue light is associated with cocaine infusion during training and testing. However, the effect of the agonist is transient in rats that acquired cocaine responding not associated with cue light activation [334]. This work suggests that KOR agonism does not simply block the unconditioned effects of cocaine or decrease overall motivation, but rather modulates the conditioned effects of cocaine.…”

The effects of social learning on the acquisition of cocaine self-administration

“…There is not a standardized procedure for measuring the acquisition of drug self-administration in laboratory animals, but many studies include noncontingent infusions of the drug at the onset of testing, either through priming infusions or autoshaping procedures, and then permit the animal to respond for contingent infusions of the drug under free-operant conditions (e.g., Campbell and Carroll, 2000; Carroll and Lac, 1993; Perry et al, 2005; Roth and Carroll, 2004; Schenk et al, 2001; Smith and Pitts, 2011; Soria et al, 2006). This method is considered to model human patterns of acquisition in which a drug is initially provided freely (such as by a friend or a dealer), and then the monetary or behavioral costs of obtaining the drug increase as the individual shifts to regular patterns of use (see review and discussion by Carroll and Meisch, 2011).…”

A single cocaine exposure enhances both opioid reward and aversion through a ventral tegmental area-dependent mechanism

“…These studies offer face validity to the relevance of sensitization processes to drug addiction. However, changes in drug self-administration behavior that follow repeated drug administration are complicated by the acute CNS effects of the self-administered drugs during testing, and the confound that increased drug intake could represent either an enhanced or reduced level of drug elicited reward (27). Furthermore, drug self-administration studies may be insensitive to treatments that concomitantly induce or enhance opposing motivational changes.…”