An Analysis of the Pharmacological Variables that Determine the Reinforcing Efficacy of Drugs Acting at Central Monoamine Systems

Abstract

The study of drugs as reinforcing stimuli has demonstrated that the variables that determine drug-taking behavior are similar between animals and humans. While it is understood that drug self-administration is controlled by numerous factors, there are pharmacological attributes of a drug that determine its ability to function as a reinforcer. In Chapter 1, data from animal models that evaluated the reinforcing and rewarding effects of monoamine agonist drugs tested as candidate treatments for cocaine addiction were compared to their abuse liability in humans and to their efficacy as therapeutics for cocaine addiction. Results from preclinical studies were highly predictive of abuse liability in humans, but not of their potential as medications. In particular, the results from self-administration studies emphasized the abuse potential of drugs acting at the dopamine (DA) system. Because of the involvement of DA in the behavioral effects of cocaine, it has been proposed that high-affinity DA transporter (DAT) inhibitors with a slow-onset and long duration of action may have potential as pharmacotherapies for cocaine addiction. These drugs can decrease cocaine self-administration, but may also have significant reinforcing effects of their own. In Chapter 2, the reinforcing strength of PTT, a drug with these pharmacological properties, was compared to cocaine using a choice procedure and a progressive-ratio (PR) schedule in rhesus monkeys. PTT was a less efficacious reinforcer than cocaine under both conditions. However, the underlying pharmacological properties that resulted in differences in the reinforcing efficacy of drugs were not evident. In Chapter 3, the pharmacological determinants of the reinforcing efficacy of several cocaine and methylphenidate analogs that differed in their pharmacokinetic and pharmacodynamic profiles were investigated using a PR schedule in rhesus monkeys. Under the conditions of this experiment, it appeared that pharmacokinetic variables were less important than the relative blockade of DAT and serotonin transporters (5-HTT) in the strength of these drugs to maintain responding. Overall, these results indicate that monoamine reuptake inhibitors with a range of pharmacological properties can exhibit reinforcing effects, and, as it pertains to DAT and 5-HTT inhibition, there is an orderly interaction between these systems that impacts drug reinforcement.