Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABA(A)-ergic ligands

Background: The general premise that receptor theory provides a useful fram ework for understanding the behavioral effects of psychoactive drugs has be en a central tenet of behavioral pharmacology. Objectives. The purpose of t his review is to reiterate this basic theme and, in particular, the proposi tion that current concepts of pharmacological efficacy can be effectively u sed to examine behavioral effects of drugs with abuse or dependence potenti al in a way that contributes to the discovery of drugs to treat drug depend ence. Experimental data: The review begins by briefly introducing the conce pt of efficacy and follows with several illustrations of how our current un derstanding 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 di fferent efficacy requirements for the discriminative-stimulus and antinocic eptive effects of mu -opioids. From a pharmacologically different perspecti ve within drug abuse research, the review continues with an exposition of e fficacy-related differences in the behavioral effects of dopamine D-1 agoni sts and how such differences might be exploited in different medications st rategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABA(A)-related antianxiety medications, and this is illustrated in a discussion of the uti lity of low-efficacy agonists in the treatment of benzodiazepine dependence . The second half of the paper provides counterpoint to the several example s of how principles of efficacy can be applied in drug discovery. The count erpoint includes, first, a critical evaluation of how the concept of effica cy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pos e for data analysis. The review ends with a discussion of efficacy-based an alysis in drug discrimination research and illustrates some of the obstacle s that may be encountered in pharmacologically classifying drugs on this ba sis. Conclusions: Ample evidence indicates that many receptor systems can b e activated in a graded manner and that principles of efficacy can be judic iously applied to understand and exploit the behavioral effects of drugs th at result from such graded activation. However, as cautioned in the last se ctions, the misapplication of pharmacological concepts in behavioral studie s of drugs may obscure their behavioral pharmacology and potentially confou nd drug discovery.