Neural Correlates of Exposure to Cocaine Cues in Rhesus Monkeys: Modulation by the Dopamine Transporter

Abstract

Background: A major goal of treatments for cocaine addiction is to reduce relapse-associated cravings, which are typically induced by environmental stimuli associated with cocaine use and related to changes in dopamine neurotransmission.

Methods: The present study used an animal model of cocaine seeking to determine functional consequences of cue exposure using fluorodeoxyglucose positron emission tomography and to relate findings to juvenile levels of dopamine transporter and D₂-like receptor availabilities determined before any drug exposure. Adult male rhesus monkeys (N = 11) self-administered cocaine (0.2 mg/kg per injection) under a second-order schedule of reinforcement, in which responding was maintained by conditioned reinforcers. Positron emission tomography scans assessing glucose utilization, a marker of functional activation, were conducted during cocaine-cue responding and food-reinforced responding in a context where cocaine was never available.

Results: Compared with the noncocaine condition, we found significant functional activation in the medial prefrontal cortex, anterior cingulate, precuneus region of the parietal cortex, and striatum-findings similar to those reported in humans who abuse cocaine. Furthermore, these functional activations in the prefrontal, cingulate, and parietal cortex measured during cocaine-cue responding were significantly correlated with juvenile measures of dopamine transporter availability, whereas no significant relationship with prior D₂-like receptor availability was observed in any brain region.

Conclusions: The similarity between the present findings and findings in humans who use cocaine supports the use of this model for examination of factors that affect the development and intensity of cue-induced drug seeking and provides evidence for potential biomarkers for the evaluation of potential treatments (behavioral and pharmacologic) for cocaine abuse.

Keywords: Cocaine; Craving; Dopamine transporters; PET imaging; Rhesus monkeys; Self-administration.