Psychological Review 1982, Vol. 89, No. 5, 507-528 Copyright 1982 by the American Psychological Association, Inc. 0033-29SX/82/8905-0507$00.75 Conditioning of Drug-Induced Physiological Responses Roelpf Eikelboom and Jane Stewart Concordia University, Montreal, Quebec, Canada An analysis of the conditioning of drug effects is presented that permits the prediction of the nature and direction of conditioned responses and accounts for drug-conditioning results within stimulus-substitution theory. It is argued that the failure to define and identify correctly the unconditioned stimulus effect and the unconditioned response effect of a drug constitutes the source of the contro- versies about the relation of the conditioned response to the observed drug effect. A model is provided for specifying the site of action of a drug with respect to feedback systems and regulatory mechanisms, and methods for identifying the site of action are discussed. The ideas presented are relevant to studies of con- ditioned drive, to drug tolerance and sensitization, and to conditioning studies that do not involve drugs. Repeated administration of drugs often results in the conditioning of physiological responses. These conditioned responses can be distinguished from other direct and in- direct drug effects by the fact that under ap- propriate circumstances, they can be elicited without administering the drug. This form of classical conditioning is important because it may occur whenever drugs are chronically administered. The drug administration ritual may act as the conditioned stimulus and come to elicit a conditioned response. These conditioned responses have been postulated to play a role in drug tolerance and sensiti- zation (Siegel, 1975b, 1977b), in drug abuse (Grabowski & O'Brien, 1981; Lynch, Stein, &Fertziger, 1976; Wilder, 1948, 1973b),and in behavioral medicine (Woods & Kulkosky, 1976). However, the reader who sets out to find an explicit role for conditioned drug ef- fects in specific situations is faced with a mass of contradictory findings and confusing in- terpretations. The most common of these This research was supported by Grant MA6678 to Jane Stewart from the Medical Research Council of Canada. Roelof Eikelboom was supported by a Bourse de 1'Enseignement Superieur from the Ministere de 1'Education, Gouvernement du Quebec. Roelof Eikelboom is now at the McGill University— Montreal Children's Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3. Requests for reprints should be sent to Jane Stewart, Department of Psychology, Concordia University, 1455 de Maisonneuve Blvd., Montreal, Quebec, Canada H3G IMS. concerns the relation between the condi- tioned response and the observed drug effect. In some cases the conditioned response is similar to the observed drug effect; in others it appears to oppose or to be in a direction opposite to that of the observed drug effect. At present there appears to be no way to pre- dict a priori the nature and direction of the conditioned response. Although the com- plexity of drug effects no doubt contributes to this situation, it is the failure to define and identify correctly the unconditioned stimulus and unconditioned response and to deter- mine their relation to the observed drug ef- fect that is the source of the apparent con- tradictions and confusions. An analysis of the conditioning of drug effects will be presented here, and a model permitting a resolution of the difficulties described will be offered. Some of the ideas developed here are based on suggestions made previously by Obal (1966) and by Wilder (1973a). Theories of Conditioning One of the oldest theories of conditioning, still widely held (Mackintosh, 1974), is the stimulus-substitution theory first suggested by Pavlov (1927/1960). Pavlov suggested that an initially neutral stimulus, the con- ditioning stimulus, through pairings comes to elicit responses normally elicited by the unconditioned stimulus; that is, the condi- tioned stimulus comes to substitute for the unconditioned stimulus. Stimulus-substitu- 507