This is an application for an ADAMHA Research Scientist Award. A program of research is proposed for characterizing the behavioral effects of two types of drugs of major clinical, social, and theoretical importance: opioids, which have long represented a significant abuse problem, and caffeine, which is the most widely consumed behaviorally-active compound in this country. A theme central to the entire research program is that through systematic and comprehensive behavioral studies it will be possible to characterize the bases of drug actions at the neuronal level. Representative opioid alkaloids--agonists, agonist/antagonists, and antagonists--will be studied in several behavioral procedures, notably, drug discrimination, food-reinforced operant responding (punishment paradigm), and locomotor activity, and in at least two animal species, rat and squirrel monkey for optimal assessment of the generality of experimental findings. Emphasis will be placed on clarifying the role of endogenous opioid peptides in the diverseness of the behavioral effects of opioid alkaloids. Behavioral effects of peptides will be determined after central administration, their effects compared to those of prototypic alkaloids, and interactions studied between peptides administered centrally and alkaloids administered systemically. The effects of chronic caffeine administration will be characterized by an integrated behavioral and neurochemical approach. Most studies will be performed on rats receiving caffeine daily by scheduled access to water bottles containing the drug. Matched controls will receive drug-free tap water. Rate and extent of tolerance development, and time course for loss of tolerance to caffeine-induced stimulation of motor activity will be determined as a function of daily drug dosage. Pharmacologic (i.e., alkylxanthine and nonxanthine drugs) and behavioral (i.e., food-reinforced operant responding) variables in tolerance to caffeine will also be assessed. Changes in various measures of the functional state of brain catecholamine and adenosine systems will be determined in parallel with the behavioral changes as a first step toward identifying the cellular mechanisms that underlie tolerance to caffeine.
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