This research will investigate behavioral and pharmacological variables that modify the development and expression of tolerance to the behavioral actions of morphine and related opioids. The experimental methods of behavioral pharmacology will be used to identify ways in which the tolerance produced by acute or chronic opioid administration can be manipulated. The behavioral end-points assessed will include effects on ongoing rates and patterns of schedule-controlled behavior, the discriminative stimulus functions of opioids, and the reinforcing functions of opioids. Preliminary studies have found that the initial behavioral consequences of morphine exposure can influence the course of behavioral tolerance development. We will extend these studies by examining behavioral tolerance development under a wider range of pharmacological and environmental conditions. Specific experiments will first assess the rate and degree of the development and loss of behavioral tolerance during chronic osmotic infusions of opioids. Tolerance development will be characterized as a function of the maintenance opioid employed (morphine or etorphine), and its dose and duration of administration. Subsequent studies will assess the degree of cross-tolerance to other opioids, and will evaluate the contributions of behavioral variables (practice factors and the reinforcement consequences of initial morphine exposure) to the rate and degree of tolerance to morphine's rate-altering effects. The roles of pharmacological and behavioral factors in the development of tolerance to the discriminative stimulus properties of morphine will be examined by comparing changes in generalization functions after selected chronic opioid dosing regimens. Similar studies will assess the rate, degree, and specificity of any tolerance to the reinforcing properties of opioids during chronic opioid administration. Such identification of the behavioral consequences of long-term opioid administration, and of the ways such consequences can be modified by both pharmacological and psychological factors, may have implications for our understanding of both of tolerance processes in general and of the factors underlying opiate abuse.
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