This is a renewal application for a NIDA Research Scientist Award. A program of research is proposed for studying behavioral effects of two types of drugs of significant clinical, social, and theoretical importance: 1) opioids, some of which have long represented a serious abuse problem; 2) caffeine, the most widely consumed behaviorally-active drug in the world, which has features that make it a convenient model """"""""drug of abuse"""""""". The proposed experiments will be supported by two research grants from NIDA. The basic research strategy is to use behavioral methodologies as bioassays of drug interactions with their neuronal substrates in order to identify and characterize components of drug action that might be relevant to potential for abuse and to related phenomena, such as tolerance and physical dependence. Representative compounds will be studied over a range of doses in several complementary behavioral procedures, such as drug discrimination, locomotor activity, autotitration of reinforcement threshold for electrical stimulation of the brain, and drug-induced turning. Established collaborations with faculty colleagues will bring additional methodologies to bear on the research questions of interest. Most experiments will be performed on rats, some on squirrel monkeys. This approach will help in the interpretation of experimental findings by indicating their generality with respect to pharmacological, behavioral, and species variables. The proposed experiments will address several hypotheses. Among them are: 1)Brain opioid systems can, under some conditions, modulate brain dopamine systems and behavioral effects of drugs that are mediated by dopamine. 2) Single-dose opioid agonist-induced sensitization to effects of antagonists is a model of acute physical dependence. 3) Discriminative effects of low and high doses of caffeine model, respectively, positive and negative mood states induced by caffeine in humans. 4) Brain dopamine systems mediate some behavioral effects of caffeine and tolerance to those effects, sometimes as a result of adenosine-receptor blockade. Several pre- and postdoctral trainees will participate in this research program each year. An important goal will be to provide them with technical and, most important, intellectual skills necessary for careers in research on the behavioral pharmacology of drugs of abuse.
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