Repeated administration of many psychoactive drugs results in diminished effectiveness of the drug, a phenom-

Repeated administration of many psychoactive drugs results in diminished effectiveness of the drug, a phenomenon named tolerance. A great deal of research has shown that associative learning contributes to tolerance (see Siegel & Ramos, 2002, for a recent review). Siegel (1975) proposed a model of tolerance in which drug administration was seen as an example of Pavlovian or classical conditioning. Environmental or contextual cues present when the drug is taken are conditioned stimuli (CSs), and the drug is the unconditioned stimulus (US). Compensatory conditioned responses (CRs) develop to counteract the effects of the drug, which are the unconditioned responses (URs). These compensatory CRs are opposite to the drug effects and help maintain homeostasis. More recent versions of this theory have maintained that the URs are not the drug effects but rather the compensatory responses (Ramsay & Woods, 1997; Siegel & Allan, 1998). In either case, environmental CSs elicit compensatory CRs, which mediate tolerance. Poulos and Cappell (1991) also proposed that compensatory responses to drugs occur to preserve homeostasis but emphasized behavioral contingencies rather than classical conditioning. Baker and Tiffany (1985) proposed a classical conditioning model in which habituation, not compensatory CRs, mediates tolerance. Paletta and Wagner (1986) suggested that, depending on the particular drug effect, either compensatory responding or habituation is the mechanism of classically conditioned tolerance. Although these theories differ somewhat as to the underlying process, all propose that environmental cues mediate tolerance. Contextual control of tolerance has been demonstrated with many drugs, including morphine (Siegel, 1975, 1977), ethanol (Brooks, Karamanlian, & Foster, 2001; Mansfield & Cunningham, 1980; Siegel, 1987), and some benzodiazepines (Greeley & Cappell, 1985; Griffiths & Goudie, 1986; King, Bouton, & Musty, 1987). In addition, contextual control of tolerance to many different effects of these drugs has been demonstrated (see Siegel, Baptista, Kim, McDonald, & Weise-Kelly, 2000, for a review). Numerous studies have demonstrated conditioned tolerance to the effects of morphine, including analgesia (Siegel, 1975), hyperthermia (Siegel, 1978), and sedation (Fanselow & German, 1982). Conditioned tolerance has been shown to the hypothermic (Mansfield & Cunningham, 1980) and ataxic (Brooks et al., 2001) effects of ethanol as well as the sedative (King et al., 1987) and hypothermic (Greeley & Cappell, 1985) effects of benzodiazepines. Many studies have also determined that conditioned tolerance conforms to the principles of classical conditioning found in traditional preparations. Contextual drug tolerance is subject to latent inhibition (Siegel, 1977), conditioned inhibition (Siegel, Hinson, & Krank, 1981), overshadowing (Walter & Riccio, 1983), sensory preconditioning, and blocking (Dafters, Hetherington, & McCartney, 1983). In addition, contextual tolerance can also be extinguished if the contextual cues are presented without the drug. Numerous studies have shown extinction of contextual tolerance to various effects of several drugs, including the analgesic effect of morphine (MacRae & Siegel, 1987; Millin & Riccio, 2002; Siegel, 1975; Siegel, Sherman, & Mitchell, 1980), the hyperthermic effect of morphine (Siegel, 1978) and of ethanol (Mansfield & Cunningham, 1980), the ataxic effect of ethanol (Brooks et al., 2001; Siegel, 1987), and the sedative effect of midazolam (King et al., 1987) and of morphine (Fanselow & German, 1982). Contextual tolerance has also been demonstrated with nicotine. Caggiula and his colleagues have shown that We dedicate this article to the memory of Jim McConnell. This research was funded by a College of Arts and Sciences Support and Development Award to the first author. Correspondence concerning this article should be addressed to J. L. Azorlosa, Department of Psychology, Peoples Building, West Chester University of Pennsylvania, West Chester, PA 19383 (e-mail: [email protected]). Acquisition and extinction of conditioned nicotine analgesic tolerance