The aims are firstly, to explore the characteristics of behavior based on the discriminative stimulus effects of drug mixtures and secondly, to investigate whether methods derived from work on mixtures can be applied to clarifying the mode of action of single drugs with multiple effects. Most drug discrimination studies focus almost exclusively on single drugs, whereas the abuse of mixtures of more than one drug at a time is a widespread health problem. Both mixtures of drugs and single drugs with multiple effects may be discriminated as a stimulus complex consisting of two or more elements and studies will clarify ways in which such compound, interoceptive stimuli are processed. The work will build upon knowledge gained in recent years from studies of the discriminative stimulus effects of mixtures and will emphasize mainly the effects of behavioral variables on the characteristics of such discriminations in rats. The influence of both the current conditions and of behavioral variables on the characteristics of such discriminations in rats. The influence of both the current conditions and of behavioral and pharmacological histories will be examined. The behavioral variables will include the alternative responses available in operant conditioning procedures for assessing discriminative effects and the consequences of devaluing the discriminative significance of stimulus elements by overshadowing, psychological blocking, and extinction procedures. The specificity of discriminative stimuli trained in different ways with mixtures of abused substances such as amphetamine and pentobarbital will be evaluated in generalization tests with pharmacologically similar drugs and drug mixtures, and with compounds from other pharmacological classes. Other studies will examine the role of a pharmacological variable, the time- course of drug action, in controlling overshadowing (which in turn contributes to the pharmacological characteristics of drug discriminations). The effects of a previous history of exposure to particular training conditions will be compared with the effects of drug exposure alone to elucidate the interacting roles of behavioral history and pharmacological history as determinants of discriminative responses to abused drug mixtures. Later studies will examine applications of the methods to single drugs with multiple effects; principles emerging from the previous and the future work on the project will be applied to the discrimination of the opioid cyclazocine and the hallucinogen lysergic acid diethylamide (LSD), each of which may bring about its effects through actions on more than one type of receptor. Novel drug discrimination procedures that have been developed in previous work on the project include ways of training discriminations that may enhance pharmacological specificity (the so-called AND-OR discrimination procedure). The practical value of these methods, and of cue manipulation by means of overshadowing, blocking and extinction procedures, will be assessed in experiments that will attempt to elucidate the role of kappa opioid and phencyclidine receptors in responses to cyclazocine, and of 5-HT/2 and dopamine receptors in responses to LSD. These experiments are, however, presented primarily as a way for developing novel methodologies that may be applicable to drugs from many classes, rather than as investigations in depth on cyclazocine and LSD.
