Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands.

Abstract

The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of mu-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.