Drug discrimination in neurobiology

Areas of neurobiological interest are identified towards which drug discrimination (DD) studies have made important contributions. DD allows ligand actions to be analyzed at the whole organism level, with a neurobiological specificity that is exquisite and often unrivalled. DD analyses have thus been made of a vast array of CNS agents acting on receptors, enzymes, or ion channels, including most drugs of abuse. DD uniquely offers access to the study of subjective drug effects in animals, using a methodology that also is transposable to humans and has generated unprecedented models of pathology (e.g., chronic pain, opiate addiction). Parametric studies of such independent variables as training dose and reinforcement provide refined insights into the dynamic psychophysiological mechanisms of both drug effects and behavior. Three different mechanisms have been identified by which discriminative, and perhaps other behaviors, can come about. DD also is superbly sensitive to small, partial activation of molecular substrates; this has enabled DD analyses to pioneer the unravelling of molecular mechanisms of drug action (attributing, f.ex., LSD's particular subjective effects to an unusual, partial activation of 5-HT, and perhaps other receptors). DD has both oriented and served as a tool to conduct drug discovery research (e.g., pirenperone-risperidone, loperamide). The DD response arguably constitutes a quantal, rather than graded, variable, and as such allows a comprehension of molecular, pharmacological, and behavioral mechanisms that would have been otherwise inaccessible. Perhaps most important are the following further contributions. One is the notion that particular, different levels of receptor activation are associated with qualities of neurobiological actions that also differ and are unique, this notion arguably constituting the most significant addition to affinity and intrinsic activity since the earliest theoretical conceptions of molecular pharmacology. Another contribution consists of studies that render redundant the notion of tolerance and identify fundamental mechanisms of signal transduction; these mechanisms account for apparent tolerance, dependence, addiction, and sensitization, and appear to operate ubiquitously in a bewildering array of biological systems.