NEURAL BASIS OF BEHAVIORAL SENSITIZATION

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION: (Applicant's Abstract) It is frequently acknowledged that environmental and psychological factors can have a large effect on the response to addictive drugs, i.e., what has been described as "set and setting" are important determinants of drug use and abuse in humans. There has been, however, little systematic research on how environmental conditions influence drug effects in animal models, and there has been almost no research on the neurobiological mechanisms by which environmental stimuli modulate the pharmacological effects of drugs. In preliminary studies we have found that the environment where animals receive psychostimulant drugs, such as amphetamine (AMPM) or cocaine, whether it is at "home" or in a "novel" environment, can have a profound effect on both their acute psychomotor response and the increase in their psychomotor effects seen with repeated drug administration (i.e., sensitization), even when the two environments are physically identical. Indeed, in one study the unsignalled intravenous (i.v.) administration of AMPH in a HOME environment failed to induce sensitization at all, whereas in a NOVEL environment the same dose induced robust sensitization. The aim of this application, therefore, is to characterize the influence of these environmental factors on the psychomotor effects of AMPH and cocaine, and especially on their ability to produce sensitization, and to begin to explore the neurobiological mechanisms by which environmental factors exert their effects. Three different series of experiments are proposed. The aim of the first series of experiments is to study dose-effect relations for i.v. administered AMPH or cocaine to systematically characterize the influence of environment (HOME vs. NOVEL), i) on the acute psychomotor response to AMPH and cocaine, ii) on the induction of sensitization, iii) on the magnitude of sensitization, and iv) on the persistence of sensitization. Experiments are also proposed to determine the influence of route of administration and potential pharmacokinetic factors. The second series is to begin to explore the neurobiological mechanisms by which environmental stimuli control drug-induced psychomotor activation and sensitization. In particular, it will determined whether environmental stimuli modulate these drug effects by modulating their ability to increase the extracellular concentration of dopamine in the nucleus accumbens, as assessed by microdialysis sampling. The third series of experiments will seek to identify those features of HOME vs. NOVEL environments responsible for their effects. In particular, we will explore the action of novelty as a "stressor", the role of familiarity, and the role of conditional stimuli. It is suggested that the studies proposed here have the potential to provide new insights into how the pharmacological and neurobiological actions of addictive drugs are influenced by environmental and psychological factors, and thus, into the neurobiology and psychology of addiction.