Investigating Dopaminergic and Opioidergic Mechanisms of Cocaine Conditioned Reinforcement Using the New Response Acquisition Procedure

Abstract

Substance use disorders are chronically relapsing conditions, such that risk of relapse can persist for years despite maintained drug abstinence. Exposure to cues associated with drug-taking can elicit feelings of intense drug-craving in humans and drug-seeking behaviors in animal models. When neutral cues in the environment are paired repeatedly with drug-taking behavior, cues and drug form associations and acquire conditioned reinforcing properties. Elucidating the neurobiological mechanisms underlying conditioned reinforcing properties may help identify novel treatments for relapse. The dopaminergic and the opioidergic systems, have been implicated as mediators of cue-induced behaviors.

The experiments described in this thesis sought to delineate the role of dopaminergic and opioidergic systems in a stringent assay measuring the conditioned reinforcing properties of cocaine-paired cues. The New Response Acquisition procedure tests the ability of cocaine-paired cues to support new learning. New Response Acquisition begins with a Pavlovian Conditioning phase, in which rats receive noncontingent infusions of cocaine either with simultaneous (Paired) or separate (Unpaired) presentations of an arbitrary stimulus. Only in Paired conditions should the cue form an association with cocaine and develop conditioned reinforcing effects. In the second phase, called Acquisition, all subjects are allowed to make a novel, operant response to produce presentations of the stimulus alone. It is expected that Paired cues induce more responses than Unpaired cues, indicative that conditioned reinforcement has occurred.

Following the establishment and optimization of a cocaine New Response Acquisition procedure, we assessed the role of dopamine in contributing to the behavior to earn cues. Dopamine levels in the nucleus accumbens shell or core were not different between groups of rats that underwent Paired or Unpaired Pavlovian Conditioning. Further, increasing dopamine levels by the administration of local or systemic indirect dopamine agonists did not potentiate responding for cues. Together, these data suggest dopamine does not mediate the reinforcing effects of cocaine-paired cues in this procedure.

To characterize the role of the opioidergic system in cocaine conditioned reinforcement, we examined the extent to which activation of opioid receptors alters responding for cues. Endogenous opioid peptides, specifically enkephalins, robustly increased responding for cocaine-paired cues, and this effect was antagonized by pretreatment of a delta opioid receptor selective antagonist. Further, activation of delta opioid receptors via direct agonists potentiated responding for cues, suggesting this system may mediate the conditioned reinforcing properties of cocaine-paired cues in New Response Acquisition.

Overall, I found that behavior maintained by cocaine-paired cues in the New Response Acquisition procedure may be modulated by the opioidergic system and is not dependent on dopamine. The work presented in this dissertation provides novel evidence for the mechanisms of cocaine conditioned reinforcement and potential new targets for reducing the ability of cues to elicit behavior and treating relapse.