La enfermedad de Parkinson Preguntas y Respuestas sobre la enfermedad de Parkinson Las personas que sufren la enfermedad deParkinson a menudo están buscando respuestasa sus preguntas acerca de cómo vivir mejor conla enfermedad. Este folleto es una recopilaciónde las preguntas más frecuentes que recibimos através de nuestro Servicio de Información sobrela enfermedad de Parkinson (PINS, por sussiglas en inglés) de parte de personas enfermasde Parkinson, sus familiares, y sus cuidadores.
Pii: s1064-1297(02)00230-4Experimental and Clinical Psychopharmacology Copyright 2002 by the American Psychological Association, Inc.
2002, Vol. 10, No. 3, 162–183 Applying Laboratory Research: Drug Anticipation and the Treatment of Drug Addiction Shepard Siegel and Barbara M. C. Ramos McMaster University Basic research concerning drug tolerance and withdrawal may inform clinical practice, andvice versa. Three areas that integrate the work of the laboratory and the clinic are discussed:(a) drug overdose, (b) cue exposure treatment of addiction, and (c) pharmacological treatmentof withdrawal symptoms. The areas are related in that they indicate the contribution ofdrug-paired cues to the effects of addictive drugs and the role of Pavlovian conditioning ofdrug effects in drug tolerance and withdrawal symptoms.
The concerns of the laboratory researcher often seem overdose, it has been clear, since the pioneering work of esoteric to the clinician. For example, the laboratory scien- Brecher (1972), that overdose is a misnomer in describing tist might be enthusiastic about a ﬁnding that opiate toler- the cause of death in heroin addicts. Most of the deaths are ance is correlated with c-Fos expression in the striatum of not due to a pharmacological overdose, as the term usually the rat's brain (Baptista, Siegel, MacQueen, & Young, is understood. Brecher summarized the extensive literature 1998), but the clinician likely would ﬁnd little in these that existed 30 years ago: "(1) The deaths cannot be due to results relevant to the treatment of opiate addiction in peo- overdose. (2) There never has been any evidence that they ple. Similarly, the clinician may be intrigued by the case are due to overdose. (3) There has long been a plethora of report of a palliative-care patient, tolerant to the analgesic evidence demonstrating they are not due to overdose" (p.
effect of oral morphine, who suffered an overdose when 102, italics in original). Results of subsequent research switched to transdermal fentanyl (Johnson & Faull, 1997).
conﬁrmed Brecher's conclusions, and it has been suggested This singular observation, however, probably would not that "the term ‘overdose' has served to indicate lack of appear immediately relevant to the researcher studying fun- understanding of the true mechanism of deaths in fatalities damental processes of opiate effects in nonhuman animals.
The purpose of this article is to indicate the relationship of directly related to opiate use" (Greene, Luke, & DuPont, these, and other, experimental and clinical observations— 1974, p. 175), and "continued utilization of the term ‘over- that is, to emphasize the symbiotic relationship between the dose' to cover all heroin-related fatalities may be counter- researcher and the clinician.
productive in developing strategies to reduce the morbidityand mortality associated with heroin" (Darke & Zador, Three Areas of Interrelated Experimental 1996, p. 1770). Despite the likely misuse of the word, we and Clinical Research continue to use the generally accepted term overdose whenreferring to these enigmatic fatalities, rather than more In this article we summarize three areas of interrelated cumbersome alternatives such as "an idiosyncratic reaction research that integrate the work of the laboratory and the to an intravenous injection of unspeciﬁc material(s) and clinic: drug overdose, cue exposure treatment of addiction, probably not a true pharmacologic overdose of narcotics" and pharmacological treatment of withdrawal symptoms.
(Cherubin, McCusker, Baden, Kavalier, & Amsel, 1972, p.
Drug Overdose Despite the fact that pronounced tolerance develops to the Many addicts die shortly after injecting heroin. Although respiratory depressive effects of opiates, the heroin over- it has been conventional to attribute such deaths to heroin dose victim typically dies of respiratory depression. Inas-much as the victims of overdose typically are not novice Shepard Siegel and Barbara M. C. Ramos, Department of Psy- users (e.g., Darke & Zador, 1996), it would be expected that chology, McMaster University, Hamilton, Ontario, Canada.
they would have been very tolerant to heroin and thus would The research from Shepard Siegel's laboratory summarized in have self-administered a very large dose when they over- this article was supported by National Institute on Drug Abuse dosed. However, postmortem examinations of heroin over- Grant DA11865, Natural Sciences and Engineering Research dose victims often do not reveal very high levels of opiate Council of Canada Grant 00298, and a grant from the Alcoholic in their system. For example, Monforte (1977) found that Beverage Medical Research Foundation. We express appreciation about three quarters of the victims of heroin overdose had to Doreen Mitchell, who assisted with much of the research sum- blood levels of morphine no higher than those seen in a marized in this article, and to Lorraine Allan for comments on control group of heroin addicts who died as a result of drafts of this article.
homicide (rather than heroin overdose): "One must con- Correspondence concerning this article should be addressed to Shepard Siegel, Department of Psychology, McMaster University, clude that in the great majority of cases death was not a Hamilton, Ontario L8S 4K1, Canada. E-mail: firstname.lastname@example.org result of a toxic quantity of morphine in the blood" (p. 720).
SPECIAL ISSUE: APPLYING LABORATORY RESEARCH What does account for these deaths? Basic psychopharma- Any therapeutic approach, whether it be insight, behaviorally cology research, with mice and rats, has elucidated a cause or pharmacologically oriented, that does not recognize thepowerful evocative effects of interoceptive and exteroceptive for at least some overdoses that has implications for mini- stimuli on craving and alcohol acquisition behavior and that mizing death among drug abusers.
neglects to provide techniques for modifying the strength ofthese effects will likely be destined to failure. (p. 547) Cue Exposure Treatment of Addiction Recognition of the evocative effects of drug-associated "It has long been recognized that the processes of ‘de- stimuli has encouraged the development of treatments that toxiﬁcation' and physical withdrawal are not the major incorporate systematic exposure to these stimuli (see Chil- impediments to effective drug-abuse treatment. Rather, the dress, McLellan, & O'Brien, 1986; Siegel, 1988, 1999a)— problem is relapse following completion of the withdrawal so-called cue exposure treatment. Results of laboratory re- crisis" (Siegel, 1999a, p. 1113). Early addiction commen- search suggest techniques to improve the efﬁcacy of cue tators noted that craving and relapse occur in response to exposure treatment.
cues that, in the past, have been associated with drug use.
Over the years, many clinicians have rediscovered the im- portance of environmental cues to relapse. For example, in of Withdrawal Symptoms The Anatomy of Drunkenness, Macnish (1859) noted thefollowing: A deﬁning characteristic of addiction is the appearance of drug withdrawal symptoms when drug use terminates.
Man is very much the creature of habit. By drinking regularly These symptoms may occur long after the last drug admin- at certain times he feels the longing for liquor at the stated istration and may be one reason for relapse. A drug that return of these periods—as after dinner, or immediately be-fore going to bed, or whatever the period may be. He even ameliorates these symptoms would be a useful addiction ﬁnds it in certain companies, or in a particular tavern at which treatment tool. Most pharmacotherapies to treat withdrawal he is in the habit of taking his libations. (p. 151) symptoms involve drug substitution, such as methadone forthe treatment of heroin addiction and nicotine patches for When the Harrison Narcotics Act was implemented in the treatment of smoking. Some pharmacotherapies, how- 1915, and the United States government established addic- ever, are designed to decrease withdrawal severity without tion treatment facilities for the then newly criminalized the complications of continued addictive drug use. For addicts, the problem of cue-elicited relapse quickly became example, both N-methyl-D-aspartate antagonists and ago- apparent. Lawrence Kolb was an Assistant Surgeon General nists for speciﬁc serotonin receptors have been used in the of the United States Public Health Service and the ﬁrst treatment of alcoholism (Bisaga & Popik, 2000).
superintendent of the then newly established Service's hos- Results of recent laboratory research suggest that a class pital for addicts in Lexington, Kentucky. He observed that of drugs that function as antagonists of a particular neu- merely enforcing abstinence during the period of with- ropeptide, cholecystokinin-8 (CCK), "might be of value in drawal distress was not an effective treatment: the treatment and prevention of relapse in opiate addicts"(Lu, Huang, Liu, & Ma, 2000, p. 832). Although there are We see this plainly exempliﬁed in the cured tobacco smoker.
. . A cured smoker who usually does not crave tobacco may some studies of the relationship between CCK activity and feel an intense desire resembling hunger when he gazes on a opioid effects in humans (e.g., McCleane, 1998), the re- box of cigars or sits in the company of friends who are search concerning CCK antagonists as a pharmacotherapy smoking. (Kolb, 1927, p. 39) for addiction has been conducted primarily with mice Kolb noted a similar phenomenon in opiate addicts: (Rezayat, Azizi, & Zarrindast, 1997) and rats (e.g., Kim &Siegel, 2001; Lu et al., 2000; Roques & Noble, 1996). The Nearly all of those who have abstained from narcotics for potential for treating drug withdrawal symptoms by modu- several months report that they have no desire for the drugs lating CCK activity is a very recent area of research that unless they see someone else take them or unless they asso- may ﬁnd application in the treatment of human addicts.
ciate with other addicts in situations which they formerlyenjoyed. (Kolb, 1927, p. 40) Pavlovian Conditioning—A Framework for Subsequently, many other clinicians have described ex- Integrating Laboratory and Clinical Findings amples of patients who display withdrawal symptoms andcrave drugs when confronted with cues that had signaled the One framework for integrating clinical and laboratory drug in the past, for example, seeing the paraphernalia of work in all three areas described earlier was provided by the addiction such as a syringe and tourniquet (e.g., Teasdale, insightful comments of a heroin addict. This 36-year-old 1973), returning to an old neighborhood following a pro- man, in describing the circumstances in which he experi- longed period of incarceration and abstinence (e.g., Kissen, enced withdrawal symptoms, "likened himself to one of 1983; O'Brien, 1976), discussing drugs with others (e.g., Pavlov's dogs" (Biernacki, 1986, p. 115). He appreciated Wikler, 1977), or even seeing actors seeming to inject that Pavlovian conditioning contributed to his drug effects.
heroin in a movie (Biernacki, 1986, p. 115). As Ludwig, Although this man likely reached his conclusion on the Wikler, and Stark (1974) noted some years ago with respect basis of introspection rather than a reading of the scientiﬁc to alcoholism treatment: literature, there is, in fact, extensive research indicating the role of conditioning in addiction. We brieﬂy review thiswork before discussing the application of the ﬁndings todrug overdose, cue exposure treatment, and pharmacologi-cal treatment of withdrawal symptoms.
What Is Pavlovian Conditioning? Ivan Petrovich Pavlov won the Nobel Prize for physiol- ogy in 1904. He was awarded the prize for his studies ofdigestive reﬂexes in dogs, using chronic observationalmethods (i.e., digestive reﬂexes were observed in intact,awake dogs). Because he used chronic preparations, Pavlovmade some observations that, although not the basis for hisNobel Prize, would be the topic of his research for theremainder of his life.
In his Nobel Prize acceptance speech Pavlov did not discuss the gastrointestinal work that formed the basis of theaward. Rather, he presented an address entitled "The FirstSure Steps along the Path of a New Investigation." The"new investigation" was the study of what we now call"conditional reﬂexes." Pavlov, then 55 years old, essentiallyabandoned his successful study of digestive physiology todevote his full energies to this new topic— one that heconsidered even more important (see Babkin, 1949).
Pavlov observed that his dogs displayed digestive re- ﬂexes (such as gastric secretion), not only in response tostimuli that had reﬂexively elicited such responses (i.e.,stimulation of receptors in the stomach) but also in responseto stimuli that, in the past, had signaled such stimulation(e.g., the presence of the person who fed the dog). Pavlovconcluded that it would be impossible to understand diges- Schematic representation of Pavlovian conditioning of tive physiology without understanding the role of these the salivary response (A), conditioning of the cardiac effects of psychic reﬂexes (as they were originally termed), as well as epinephrine by Subkovand Zilov(1937; B), and conditioning physiological reﬂexes. He developed procedures and termi- compensatory responses to drugs (C).
nology that are used today in the study of Pavlovianconditioning.
small amounts of food or dilute acid was injected into their The Pavlovian Conditioning Paradigm mouth. Such stimulation of receptor cells in the mouthinitiates activity along the trigeminal and glossopharyngeal Pavlovian conditioning (sometimes termed respondent, nerves to medullary salivary centers, which results in effer- classical, or Type 1 conditioning) is deﬁned by a set of ent neural activity, transmitted to salivary glands in the operations in which a neutral conditional stimulus (CS) is mouth, eliciting salivation—the UCR. The CS was some paired with a biologically signiﬁcant unconditional stimulus arbitrary cue (such as a tone of a certain pitch). After some (UCS). At the start of conditioning, the UCS reﬂexively pairings of CS and UCS, a new reﬂex developed—the tone (i.e., unconditionally) elicits some response, termed the elicited salivation: "The activity of the salivary gland has unconditional response or unconditional reﬂex (UCR). The thus been called into play by impulses of sound—a stimulus UCR is the response of the central nervous system to the quite alien to food" (Pavlov, 1927, p. 22).
UCS. As a result of CS–UCS pairings, the CS becomesassociated with the UCS. The acquisition of this association Drug Administration as a Conditioning Trial is revealed by the emergence of a new response to thepreviously neutral CS. Because this new response is condi- Pavlov (1927, p. 35) suggested that the administration of tional on CS–UCS pairings, it is termed the conditional a drug could be viewed as a conditioning trial; stimulation response or conditional reﬂex (CR). Pavlov realized that of receptors sensitive to the drug served as the UCS and the salivation was much easier to measure than gastric secretion immediately antecedent environmental cues served as and that the manipulation of cues such as tones and lights CSs. The development of conditional pharmacological re- could be much more precise than manipulation of cues such sponses can be ascertained merely by presenting the CS as the sight of the person that normally fed the dogs.
(predrug cues) without the UCS (the drug), that is, by Pavlov's well-known conditioning preparation is sche- administering an inert substance in the usual drug-adminis- matically illustrated in Figure 1A. Dogs were presented with SPECIAL ISSUE: APPLYING LABORATORY RESEARCH Subkovand Zilov(1937) provided an early demonstra- stimulus (external inhibition) or by altering the putative CS tion of pharmacological conditioning. Their preparation is (changing the context for each successive drug administra- schematically illustrated in Figure 1B. Subkovand Zilov tion in an unpredictable manner). The acquisition of toler- injected dogs with epinephrine (adrenaline) on a number of ance is retarded by partial reinforcement, preexposure to the occasions. Epinephrine stimulates ␤ adrenoceptors in the CS, and inhibitory learning. Like other conditional re- sinoatrial node of the right atrium of the heart (hence sponses, drug tolerance displays extinction, spontaneous increasing blood pressure and heart rate as a result of direct recovery, stimulus generalization, and a ﬂattening of the stimulation of the heart). The reﬂex response to this uncon- generalization gradient as a result of extending the interval ditional stimulation is a compensatory homeostatic response between acquisition and assessment. Tolerance also dis- (e.g., increased vagal activity) that decreases heart rate.
plays sensory preconditioning and a variety of compound Subkovand Zilov(1937) noted that, following such a series conditioning effects such as overshadowing and blocking of epinephrine injections, merely placing the dog in the (Siegel et al., 2000). One prediction of the conditioning injection stand and administering an inert substance pro- analysis of tolerance that is especially relevant to clinical duced bradycardia: issues has been termed the situational-speciﬁcity of toler-ance (Siegel, 1978, p. 345).
It follows that the mere reproduction of the experimental Results of many experiments indicate that, following a conditions in which the animal is accustomed to receive series of drug administrations, tolerance is more pro- adrenaline is alone sufﬁcient to set in motion the mechanism,by means of which the animal counteracts the high vascular nounced in the presence of the usual drug-associated cues pressure produced by adrenaline. (Subkov& Zilov, 1937, p.
than it is in the presence of alternative cues (Siegel et al., 2000). For example, Siegel, Hinson, and Krank (1978)demonstrated situational-speciﬁcity of tolerance using a In fact (as depicted in Figure 1C), many types of phar- paired– unpaired design. Rats were assigned to same-tested macological stimulation elicit UCRs that compensate for the or different-tested conditions. For same-tested rats, pretest unconditionally elicited, drug-induced disturbances. After morphine injections were signaled by an audiovisual cue.
some drug administrations, drug-compensatory responses Different-tested rats received their pretest drug injections occur in the presence of drug-administration cues. Such and cue presentations in an unpaired manner. Following the learned responses have been termed conditional compensa- last pretest injection, analgesia was assessed in the presence tory responses—CCRs (Siegel, Baptista, Kim, McDonald, of the audiovisual cue. Although same- and different-tested & Weise-Kelly, 2000). CCRs have been demonstrated with rats received the same number of morphine injections, at the respect to many effects of a variety of drugs, including same doses and at the same intervals, same-tested rats were commonly abused drugs such as opiates (e.g., Kim, Siegel, more tolerant to morphine-induced analgesia than were dif- & Patenall, 1999; Mucha, Volkovsiks, & Kalant, 1981; ferent-tested rats.
Raffa & Porreca, 1986), ethanol (e.g., Duncan, Alici, & The fact that tolerance displays situational-speciﬁcity is Woodward, 2000; Larson & Siegel, 1998; Leˆ, Poulos, & consistent with the conditioning analysis of tolerance. That Cappell, 1979), and caffeine (Andrews, Blumenthal, & is, drug-associated cues elicit CCRs that attenuate the drug Flaten, 1998; Rozin, Reff, Mark, & Schull, 1984).
effect; therefore, tolerance is greater when assessed in thepresence of drug-associated cues than when it is assessed Conditional Compensatory Responses, Drug Tolerance, and the Situational-Speciﬁcity of Tolerance Interoceptive Cues for Drugs Tolerance is said to occur when the effect of a given dose Although experimental studies of the associative basis of of a drug decreases over the course of repeated administra- tolerance typically have manipulated exteroceptive cues tions. Pavlovian conditioning contributes to tolerance.
(e.g., the room where the drug is administered), there is When the drug is administered repeatedly in the context of evidence that a variety of stimuli may become associated the usual predrug cues, these cues elicit a CCR that atten- with a drug and control the display of tolerance. For exam- uates the drug effect. As the drug is administered more and ple, distinctive ﬂavors, ambient temperatures, or magnetic more often, and the CCR grows in strength, the attenuation ﬁelds, after being paired with morphine administration, may of the drug effect becomes more pronounced.
inﬂuence the display of morphine tolerance (Siegel et al., The extensive evidence that conditioning contributes to 2000). Especially relevant to clinical applications are results tolerance recently has been reviewed (see Siegel et al., indicating that two categories of interoceptive cues, phar- 2000). Brieﬂy, posttrial events that affect memory consoli- macological cues and self-administration cues, may become dation similarly affect the rate of tolerance acquisition; thus, associated with a drug effect.
electroconvulsive shock or frontal cortical stimulation de-creases the rate of acquisition of morphine tolerance, and glucose facilitates the rate of acquisition of morphine tol-erance (Siegel, 1999b; Siegel et al., 2000). Furthermore, in There is considerable evidence that organisms can learn common with other conditional responses, the expression of that a stimulus, normally considered to be a UCS, signals drug tolerance is disrupted by presenting a novel external the delivery of another UCS (Goddard, 1999); thus, it is not surprising that organisms can associate two drug effects.
effect than do passively received drugs; that is, the self- There have been various types of experiments concerning administration contingency should enhance the develop- pharmacological cues for drugs (see Siegel et al., 2000). Of ment of tolerance. There are several reports that this is the special relevance are ﬁndings that a drug can serve as a cue for itself. For example, Greeley, Leˆ, Poulos, and Cappell Mello and Mendelson (1970) provided perhaps the ﬁrst (1984) demonstrated that a small dose of ethanol could demonstration of the importance of the self-administration serve as a CS for a larger dose of ethanol. In this Greeley et contingency in a drug effect. Alcoholic men were allowed to al. study, rats in one group (paired) consistently received a ingest alcohol in each of two conditions: when they wished low dose of ethanol (0.8 g/kg) 60 min prior to a high dose (spontaneous condition) or only during experimenter-deter- of ethanol (2.5 g/kg). Another group of rats (unpaired) mined intervals (programmed condition). Tolerance was received the low and high doses on an unpaired basis. When greater in the same individuals following the spontaneous tested for the tolerance to the hypothermic effect of the high condition than it was following the programmed condition.
dose following the low dose, paired subjects, but not un- More recently, Ehrman, Ternes, O'Brien, and McLellan paired subjects, displayed tolerance. Moreover, if the high (1992) evaluated the effects of 4 mg hydromorphone in dose of ethanol was not preceded by the low dose, paired detoxiﬁed opiate abusers under two conditions: when they rats failed to display their usual tolerance. This tolerance, intravenously self-administered the drug and when the drug dependent on an ethanol– ethanol pairing, was apparently was infused by the experimenter. Ehrman et al. reported that mediated by a thermic CCR; paired rats, but not unpaired several effects of hydromorphone were greater when the rats, evidenced hyperthermia (opposite to the hypothermic drug was passively received than when it was self-admin- effect of the drug) in response to the low dose of ethanol.
istered and concluded that "tolerance was observed when There also is evidence that a small dose of morphine may the subjects injected the opiate, but not when the same dose serve as a cue for a larger dose of the opiate and control the was received by unsignaled intravenous infusion" (p. 218).
display of morphine tolerance (Cepeda-Benito & Short, An especially elegant procedure for evaluating the role of 1997). Kim et al. (1999) have termed such associations, in self-administration in drug effects is the yoked-control de- which a small dose of a drug serves as a cue for a larger sign. With this design, each time a subject assigned to a dose of the same drug, intradrug associations.
self-administration (SA) group makes a particular response Several investigators have suggested that intradrug asso- (e.g., presses a lever in an operant chamber), the same ciation ﬁndings have important implications for understand- amount of drug is administered to that subject and to an- ing the contribution of conditioning to tolerance. Within other, yoked (Y), subject. Thus, both SA and Y subjects each drug administration, drug-onset cues (DOCs) reliably receive the same dose of the drug, equally often and at the precede the later, larger drug effect; thus, there is the po- same intervals. Several investigators have reported that, tential for the formation of associations whenever a drug is after some drug experience, the effects of the drug are administered (e.g., Greeley et al., 1984; King, Bouton, & greater in Y than in SA rats; that is, tolerance is less Musty, 1987; Mackintosh, 1987; Tiffany, Petrie, Baker, & pronounced in Y animals (Donny, Caggiula, Knopf, & Dahl, 1983). Results of several experiments indicate that Brown, 1995; Weise-Kelly & Siegel, 2001).
such intraadministration associations do form when a drug In sum, cues such as SACs and DOCs function as CSs.
is administered, and that DOCs, in common with extero- They become associated with the drug effect and come to ceptive cues, contribute to drug tolerance (Ce´le rier, Laulin, elicit CCRs that mediate tolerance. Thus, the fact that tol- Corcuff, Le Moal, & Simonnet, 2001; Grisel, Wiertelak, erance is especially pronounced when the drug effect occurs Watkins, & Maier, 1994; Kim et al., 1999; Mucha, Kalant, following the usual DOC (e.g., Kim et al., 1999) or SAC & Birbaumer, 1996).
(Weise-Kelly & Siegel, 2001) is but another demonstrationof the situational-speciﬁcity of tolerance. That is, situational cues that elicit CCRs may be interoceptive, as well asexteroceptive.
Typically, humans self-administer the drugs that they use.
Such self-administration is a characteristic of both illicit Pavlovian Conditioning and Drug Overdose (e.g., cocaine and heroin) and licit (e.g., nicotine and etha-nol) drug use. In contrast, in the laboratory most psycho- The most dramatic demonstrations of the situational- pharmacology researchers administer the drug to subjects.
speciﬁcity of tolerance concern tolerance to the lethal ef- Thus, much of what we know about the effects of drugs, fects of drugs. Following a series of drug administrations such as the development of drug tolerance, is based on involving escalating doses, each in the context of the same results of studies in which the experimenter—not the sub- cues, tolerance develops to the potentially lethal effect of ject—administered the drug. If drug delivery is contingent that drug as long as it is administered in the usual context.
on a response, interoceptive response-initiating (or re- Altering the context of drug administration increases the sponse-produced) cues are paired with the drug effect.
lethality of several drugs (summarized in Siegel, 2001). The Weise-Kelly and Siegel (2001) suggested that these self- ﬁndings were originally reported in studies with nonhuman administration cues (SACs) function as other CSs—that is, animals, but results of clinical research concerning opiate they come to elicit CCRs. If SACs elicit CCRs, it would be overdose in humans are consistent with the laboratory expected that self-administered drugs should have a smaller SPECIAL ISSUE: APPLYING LABORATORY RESEARCH Experiments With Rats and Mice Figure 2B summarizes results reported by Vila (1989). In this experiment, same- and different-tested rats were intra- Although there were procedural differences among the peritoneally injected with 30 mg/kg pentobarbital on 20 experiments that evaluated the role of predrug cues in drug occasions, with each injection of the barbiturate occurring in lethality, they all incorporated groups of rats or mice that a distinctive room. In a ﬁnal test session, all rats were were administered a high drug dose in a test session. Prior injected with 95 mg/kg pentobarbital. Test-session mortality to this test, some of the subjects were administered lowerdoses of the drug and received the test infusion in the same data reported by Vila and summarized in Figure 2B indicate, environment in which they received the prior infusions again, that the environment of drug-administration affected (same-tested). Other subjects had the same pretest history of drug-induced mortality. Same-tested rats were more likely drug administration as same-tested subjects but received the to survive the high dose of pentobarbital than were differ- test infusion in a different environment than that previously ent-tested rats. Indeed, chi-square analyses of the data sum- paired with the drug (different-tested). Finally, subjects in a marized in Figure 2B indicated that the mortality in pento- control group received the drug for the ﬁrst time in the test barbital-experienced different-tested rats did not differ from session. The results of three experiments that have used this that seen in pentobarbital-naı¨ve control rats: "These results procedure, with three different drugs, are summarized in indicate that the probability of pentobarbital-induced lethal- ity is substantially diminished in an environment previously Figure 2A summarizes results reported by Melchior associated with pentobarbital administration" (Vila, 1989, (1990). In her experiment, same- and different-tested mice were intraperitoneally injected with 3.5 g/kg ethanol twice Figure 2C summarizes results reported by Siegel, Hinson, per day for 4 days. The mortality in each group resulting Krank, and McCully (1982). Prior to participation in this from a 5.5 g/kg ethanol injection on the 5th day is depicted experiment, rats were prepared with chronic intravenous in Figure 2A. All same-tested mice survived the high dose cannulae. Same- and different-tested rats then received 15 of the drug. However, despite the fact that different-tested intravenous infusions of heroin. The dose was gradually mice (like same-tested mice) received ethanol for the ninth increased over the course of the infusions from 1 mg/kg to 8 time in this test session, most of them died as a result of the mg/kg. In a ﬁnal test session, all rats were infused with 15 test-session injection. It would appear that, as expected on mg/kg heroin. Once again, drug-induced mortality was sig- the basis of a conditioning analysis of tolerance, altering the niﬁcantly higher in different-tested than in same-tested sub- context of ethanol administration enhances ethanol-induced jects. Because of the large number of rats that were used in lethality: "Conditioned tolerance can provide protection this Siegel et al. (1982) study the experiment was conducted against ethanol lethality" (Melchior, 1990, p. 205).
in six replications. In every replication, a greater proportion Mean mortality in rodents administered a high dose of a drug on a test session. Prior to this test, some of the animals were administered lower doses of the drug and received the testinfusion in the same environment in which they received the prior infusions (same-tested; ST). Otheranimals had the equivalent pretest history of drug administration as ST subjects but received the testinfusion in a different environment than that previously paired with the drug (different-tested; DT).
Animals in a third group received the drug for the ﬁrst time on the test session (control group;CONT'L). Figure 2A summarizes results reported by Melchior (1990) for mice intraperitoneallyinjected with ethanol. Figure 2B summarizes results reported by Vila (1989) for rats intraperitone-ally injected with pentobarbital. Figure 2C summarizes results reported by Siegel, Hinson, Krank,and McCully (1982) for rats intravenously injected with heroin.
of different-tested than same-tested rats died—a statistically admission. The results of the Gutie´rrez-Cebollada et al.
signiﬁcant effect, using the binomial test: study are summarized in Table 1. As can be seen in Table 1,every one of the patients that recently had used heroin, but In conclusion, groups of rats with the same pharmacological had not suffered an overdose, injected the drug in their usual history of heroin administration can differ in mortality fol-lowing administration of a high dose of the drug: rats that drug-administration environment. In contrast, 52% of the received the potentially lethal dose in the context of cues overdose victims administered "in an unusual setting" (Gu- previously associated with sublethal doses were more likely tie´rrez-Cebollada et al., 1994, p. 171). Chi-square analysis to survive than animals that received the dose in the context of the interaction apparent in Table 1 was statistically sig- of cues not previously associated with the drug. (Siegel et al.,1982, p. 437) niﬁcant ( p ⬍ .0001). As summarized by Gutie´rrez-Cebol-lada et al., As indicated previously, interoceptive cues, as well as exteroceptive cues, may become associated with a drug The association between heroin overdose and unusual drugadministration setting conﬁrms the inﬂuence of non-pharma- effect and mediate tolerance. For example, SACs are im- cological factors in heroin overdosing. Further studies should portant predrug signals; thus, we might expect that a drug be considered to address the role played by self-administra- administered in the presence of the SACs should be less tion of heroin in an unusual setting in conditioned tolerance.
lethal than the same dose administered without this salient predrug interoceptive CS. Indeed, Johanson and Schuster(1981) reported that experimenter-programmed administra- Evidence in support of the conditioning interpretation of tion of phencyclidine in monkeys frequently is lethal "at tolerance is provided by studies indicating parallels between dose levels at or below those self-administered, which ani- Pavlovian conditioning and tolerance. As indicated previ- mals survived" (p. 280). More recently, Dworkin, Mirkis, ously, a variety of nonpharmacological manipulations that and Smith (1995) evaluated the effects of cocaine in SA and are known to affect the magnitude of conditional responding Y rats. Mortality was signiﬁcantly lower in SA rats (that had similarly affect drug tolerance. One that may be relevant to SACs signaling the drug effect) than in Y rats (that received overdose in humans is external inhibition. CRs, once estab- the drug in the absence of SACs).
lished, can be disrupted by the presentation of a novel,extraneous stimulus. The phenomenon was termed externalinhibition by Pavlov (1927), who described its operation in Studies of Overdoses in Humans the salivary conditioning situation: Obviously, research with humans cannot incorporate ex- The dog and the experimenter would be isolated in the ex- perimental manipulation of predrug cues in an attempt to perimental room, all the conditions remaining for a while precipitate overdose. Rather, clinical research can only ret- constant. Suddenly some disturbing factor would arise—a rospectively evaluate the conditions that prevailed on the sound would penetrate the room; some quick change in illu- occasion of an overdose and compare those conditions with mination would occur, the sun going behind a cloud; or adraught would get in underneath the door, and maybe bring the overdose victim's usual circumstances of drug admin- some odour with it. If any of these extra stimuli happened to istration. Results of such studies of human drug addicts and be introduced just at the time of application of the conditioned patients that receive medically prescribed opiates for pain stimulus, it would inevitably bring about a more or less relief are consistent with the results obtained from experi- pronounced weakening or even a complete disappearance ofthe reﬂex response depending on the strength of the extra ments with nonhuman animals—altering the context of drug stimulus. (p. 44) administration increases the risk of overdose (Siegel, 2001).
There are several demonstrations that, as expected on the Overdoses in Drug Addicts basis of a conditioning interpretation of tolerance, the ex-pression of tolerance is disrupted when a subject, displaying Siegel (1984) interviewed 10 heroin overdose survivors a small, tolerant response to a drug, is presented with a in an attempt to ascertain whether the overdoses occurred novel stimulus, for example, an unexpected noise (Larson & following novel predrug cues. For seven of the overdoses,the drug was administered in an environment not previouslyassociated with drug use. These reports are consistent withthe suggestion that administration in the presence of cues not previously associated with heroin is a risk factor for Circumstance of Heroin Administration for 76 Patients heroin overdose in humans, as it is in rats.
Who Recently Had Used Heroin and Were Admitted to a A more thorough evaluation of the contribution of drug- Hospital Emergency Room, Either for a Heroin associated cues to heroin overdose was reported by Gutie´r- Overdose or for Other Reasons rez-Cebollada, de la Torre, Ortun˜o, Garce´s, and Camı´ Reason for admission (1994). These investigators interviewed 76 heroin addicts Environment of heroin admitted to the emergency room of a university hospital in use prior to admission Barcelona, Spain: Fifty-four patients were admitted because of heroin overdose, and 22 were seeking urgent medical care for unrelated conditions, but their interview revealed Based on data from Gutie´rrez-Cebollada et al. (1994).
intravenous heroin self-administration 1 hr or less before OD ⫽ heroin overdose; Non-OD ⫽ other reasons.
SPECIAL ISSUE: APPLYING LABORATORY RESEARCH Siegel, 1998; Poulos, Hunt, & Cappell, 1988; Siegel & The patient was being attended at home and received a Larson, 1996; Siegel & Sdao-Jarvie, 1986). As discussed by morphine injection four times per day (at 6-hr intervals).
Larson and Siegel (1998), The injections had been given for 4 weeks. The patient'scondition was such that he stayed in his bedroom, which The conditioning analysis of tolerance has been shown to beimportant in understanding drug overdose. . Based on ﬁnd- was dimly lit and contained much hospital-type apparatus ings of external inhibition of tolerance, we would predict that necessary for his care. The morphine had always been if people consistently administer a drug under one set of injected in this environment. For some reason, on the day circumstances, a novel stimulus presentation or the novel that the overdose occurred, the patient dragged himself out omission of a stimulus should disrupt tolerance and result in of the bedroom to the living room. The living room was an exaggerated drug effect. (p. 141) brightly lit and different in many ways from the bedroom– Indeed, Siegel (1989) described such a case report in which sickroom. The patient, discovered in the living room by external inhibition of tolerance may have contributed to a N. E., appeared to be in considerable pain. Inasmuch as it heroin overdose. The victim (E. C.) was a heavy user of was time for his father's scheduled morphine injection, heroin for 3 years. She usually self-administered her ﬁrst, N. E. injected the drug while his father was in the living daily dose of heroin in the bathroom of her apartment, room. He had never administered the morphine in this where she lived with her mother. Typically, E. C. would environment before. N. E. noticed that his father's reaction awake earlier than her mother, turn on the water in the to this injection was atypical; his pupils became unusually bathroom (pretending to take a shower), and self-inject small, and his breathing became very shallow.
without arousing suspicion. However, on the occasion of the Alarmed by his father's reaction to this injection in the overdose, her mother was already awake when E. C. started living room, N. E. called his father's physician. The physi- her injection ritual, and she knocked loudly on the bathroom cian instructed N. E. to evaluate some indices of his father's door telling E. C. to hurry. When E. C. then injected the status. On the basis of the information supplied by the son, heroin, she immediately found that she could not breathe.
the physician concluded that his father suffered an overdose She was unable to call to her mother for help (her mother of morphine. The father died some hours later.
eventually broke down the bathroom door and rushed E. C.
In view of the patient's condition, there was no postmor- to the hospital, where she was successfully treated for tem examination to ascertain the potential role of morphine heroin overdose). Obviously, there are any number of rea- in his death. The evidence that he died from an overdose is sons why E. C. may have overdosed on this occasion, but it based on his reaction to the ﬁnal morphine administration is possible that the novel, external stimulus (mother knock- and the physician's interpretation of the symptoms as de- ing on bathroom door) disrupted the CCR usually elicited scribed in his telephone conversation with N. E. at the time by drug-associated cues.
of the event. Of course, there are a variety of possibleexplanations for this very sick patient's death. However, the Overdoses in Patients Receiving Medically symptoms immediately preceding death strongly implicate morphine overdose, and the circumstances of the death arecongenial with a Pavlovian conditioning interpretation of There are case reports of patients that were receiving this overdose. The patient's shallow breathing and con- medically prescribed opiates and, for seemingly inexplica- stricted pupils are classic symptoms of opiate overdose. The ble reasons, suffered an apparent overdose following a fact that N. E. stated that he was always assiduous in particular administration. These reports are consistent with preparing the morphine (including the preparation on the the conditioning analysis of tolerance and the failure of occasion of the apparent overdose) suggests that there was tolerance that occurs when the environment of drug admin- nothing unusual about the drug dosage on the occasion of istration is altered.
the apparent overdose.
Siegel and Ellsworth (1986) described a case of an ap- As discussed previously, a variety of cues may become parent overdose death of a patient receiving morphine for associated with a drug effect and control the display of relief of pain from pancreatic cancer. The patient's son, tolerance, including DOCs. Recall that these drug-onset N. E., regularly administered the drug in accordance with cues are the early drug effects, experienced shortly after the procedures and dosage levels speciﬁed by the patient's each administration, that reliably signal the later, larger drug physician. N. E. was 17 years old when he administered the effect. Johnson and Faull (1997) described a case of an fatal dose of morphine. Two years later, N. E. was a student apparent overdose in a patient receiving medically pre- in a class in which the Pavlovian conditioning analysis of scribed opiates that Siegel and Kim (2000) suggested may drug tolerance was discussed. It was only then that N. E.
be interpretable by a conditioning analysis of tolerance that realized the applicability of the model to his father's death incorporated the CS properties of DOCs. Johnson and and attempted to reconstruct the circumstances of the event.
Faull's patient had been treated for pain with a regimen that Many details concerning the overdose are not accessible, included oral morphine for about 3 months. Tolerance to the and some information was forgotten over the period be- analgesic effect of the drug developed. The patient opted to tween the death and N. E.'s insight into the potential role of change to transdermal fentanyl, and cross-tolerance was conditioning in the death. Nevertheless, N. E.'s interpreta- expected. Fortuitously, the morphine–fentanyl conversion tion of the event as another instance of exacerbation of a dose was incorrectly calculated and the patient received one drug effect by environmental alteration is reasonable.
quarter of the manufacturer's recommended conversion dose. Nevertheless, the patient suffered an opioid overdose.
switched from oral morphine to transdermal fentanyl (de- Johnson and Faull concluded that, despite the patient's scribed by Johnson & Faull, 1997) was subjected to peer tolerance to oral morphine, there was apparently no cross- review by the journal in which both articles appeared, tolerance to fentanyl: "If this man had received the ‘correct' Palliative Medicine. One of the anonymous reviewers of the dose [of fentanyl] as calculated from the manufacturer's Siegel and Kim submission stated, "the hypothesis that data sheet he would have experienced severe toxicity" tolerance is situation speciﬁc is a completely new one to (Johnson & Faull, 1997, p. 494).
me—and I suspect to all others actively involved in patient Although Johnson and Faull (1997) did not offer an care." Similarly, in a recent summary of the potential mech- explanation for the overdose that they noted, Siegel and anisms of heroin overdose, Zador (1999) noted, accurately, Kim (2000) did. Siegel and Kim suggested that this disrup- that "ingesting heroin in an unusual or unfamiliar setting is tion of tolerance seen following a change in route of ad- not currently publicized as a risk" (p. 976). Communication ministration is a further demonstration of the situational- between researchers and clinicians in this area needs speciﬁcity of tolerance. Among the stimuli that comprise the drug-associated cues are those cues inherent within theadministration procedure (such as DOCs). As summarized Pavlovian Conditioning and by Siegel and Kim (2000), Cue Exposure Treatment Johnson and Faull's observations concerning a failure of Drug withdrawal symptoms and drug tolerance are highly cross-tolerance to occur between two -opioid receptor ago- nists in conjunction with an alteration in administration pro- correlated (e.g., Koob, Stinus, Le Moal, & Bloom, 1989; cedure may represent another demonstration of the situa- Peper, Grimbergen, Kraal, & Engelbart, 1987). Moreover, tional-speciﬁcity of tolerance. The phenomenon has been withdrawal symptoms are compensatory responses: "As a implicated in unexpected overdose deaths resulting from opi- general pharmacological principle, it can be asserted that ates, alcohol, and pentobarbital, and may also (as Johnson andFaull's observations suggest) be relevant to understanding withdrawal effects are usually opposite to acute drug ef- and preventing enigmatic overdoses in clinical practice.
fects" (Poulos & Cappell, 1991, p. 402). According to the Pavlovian conditioning analysis, the relationship betweentolerance and withdrawal, and the fact that most withdrawal Drug Overdose: The Researcher and the Clinician symptoms are drug-compensatory responses, are attribut-able to the fact they are both manifestations of the same Situational-speciﬁcity of tolerance was originally de- conditioned compensatory drug response.
scribed in many experiments conducted by Clifford Mitch-ell and colleagues more than 40 years ago (see review by Pavlovian Conditioning and Siegel, 1978). Subsequent laboratory research has estab- Drug Withdrawal Symptoms lished the reliability of the phenomenon with respect totolerance to many effects of a variety of drugs: opiates, When the drug is administered in the context of the usual naloxone, ethanol, nicotine, pentobarbital, phencyclidine, drug-administration cues, CCRs attenuate the drug effect immunoenhancing drugs, cholecystokinin, carisoprodol, and contribute to tolerance. However, if there is no drug haloperidol and several benzodiazepines (see Siegel et al., effect (i.e., the usual cues for drug administration are 2000). The relevance of situational-speciﬁcity of tolerance present, but the usual drug is not administered), these CCRs to heroin overdose in rodents was ﬁrst demonstrated in the achieve full expression because they are not modulated by a laboratory approximately 20 years ago (Siegel et al., 1982), drug effect. Such CCRs, displayed in such circumstances, and the basic ﬁnding subsequently has been replicated with are termed withdrawal symptoms. In discussing the role of respect to overdose to nonopiate drugs (Melchior, 1990; CCRs in withdrawal symptoms, it is important to make a Vila, 1989). Results of case reports (e.g., Siegel, 1984, distinction between the acute withdrawal reaction seen 1989) and epidemiological studies (e.g., Gutie´rrez-Cebol- shortly after the initiation of abstinence (which typically lada et al., 1994) evaluating the circumstances of heroin lasts for days or, at most, weeks) and the apparently similar overdose in humans are consistent with the results of labo- symptoms often noted after detoxiﬁcation is presumably ratory experiments with mice and rats. Furthermore, the role complete (see Hinson & Siegel, 1982). In the latter case, it of environmental cues in tolerance in general, and in failures is likely that Pavlovian conditioning contributes to the of tolerance responsible for overdoses in particular, are explicable on the basis of a theoretical account of tolerance(i.e., Pavlovian conditioning) that has considerable empiri- Consider the situation in which the addict expects a drug, but cal support (Siegel et al., 2000). In short, the data and theory does not receive it; that is, no drug is available, but the addictis in an environment where he or she has frequently used implicating drug-paired cues in overdose are overwhelming drugs in the past, or it is the time of day when the drug is (Siegel, 2001).
typically administered, or any of a variety of drug-associated Nevertheless, there does not seem to be widespread dis- stimuli occur. Research with animals demonstrates that pre- semination of this information, either among clinicians who sentation of cues previously associated with drug administra-tion, but now not followed by the drug, results in the occur- treat patients with opiates for pain relief or among clinicians rence of drug-compensatory CRs. . In the situation in who deal with heroin addicts. For example, Siegel and which the drug addict expects but does not receive the drug, Kim's (2000) explanation of the overdose seen in a patient it would be expected that drug-compensatory CRs would also SPECIAL ISSUE: APPLYING LABORATORY RESEARCH occur. These CRs normally counter the pharmacological dis- extinction of these CRs may be achieved through repeated ruption of functioning which occurs when the anticipated unreinforced exposure to the CS" (Carter & Tiffany, 1999, drug is administered. However, since the expected drug is not forthcoming, the CRs may achieve expression as overt phys-iological reactions, e.g., yawning, running nose, watery eyes,sweating . . or form the basis for the subjective experience of Extinction of the Response to Drug-Associated Cues withdrawal sickness and craving. (Hinson & Siegel, 1982, p.
499) On the basis of the results of research with rats, we would expect that repeated presentations of predrug cues, in the There is much evidence that such withdrawal symptoms, absence of the drug, should extinguish CCRs. Most research seen long after the last exposure to a drug, are especially in this area has been designed to evaluate a prediction of the pronounced in the presence of drug-related cues (Siegel, conditioning analysis of tolerance. If tolerance is mediated 1999a); that is, "it is the anticipation of the drug, rather than by these CCRs, procedures that decrease the strength of the drug itself, that is responsible for these symptoms . .
Pavlovian conditioning should similarly decrease the mag- some drug ‘withdrawal symptoms' are, more accurately, nitude of tolerance. The magnitude of established CRs is drug ‘preparation symptoms'" (Siegel, 1991, p. 412). Ac- decreased by extinction, that is, repeated presentations of cording to the conditioning account of tolerance, as applied the CS without the UCS. Similarly, tolerance to the anal- to withdrawal symptoms, the CCRs elicited by the usual gesic, lethal, and behaviorally sedating effects of morphine drug-paired cues, in the absence of the usual drug, include are attenuated by repeated presentation of the predrug cues.
the readily observable drug-compensatory responses and the Similarly, tolerance to a variety of effects of ethanol, am- less readily observable neurochemical responses that are phetamine, midazolam (a short-acting benzodiazepine), and interpreted as craving (Siegel, 1999a).
the synthetic polynucleotide, Poly I:C, also can be extin- The results of many studies support clinical observations guished (see reviews by Siegel, 1999a; Siegel et al., 2000).
that predrug cues are powerful elicitors of withdrawal These ﬁndings, indicating that drug CCRs are attenuated by symptoms. The ﬁndings have been obtained in both labo- an extinction procedure, suggest that cue exposure should ratory experiments (with humans and nonhuman animals) be an effective addiction treatment strategy.
and in epidemiological studies. This literature recently has Krank and Wall (1990) reported the results of three been reviewed (Carter & Tiffany, 1999; Siegel, 1999a).
experiments that evaluated such a cue exposure treatment Brieﬂy, rats with a history of drug administration display with rats. During the self-administration phase of each ex- more behavioral withdrawal symptoms in a drug-paired periment, rats pressed a lever in an operant chamber for environment than in an alternative environment. Drug- access to a saccharin– ethanol mixture. They subsequently paired cues contribute not only to withdrawal symptoms in were denied access to ethanol during an extinction phase.
rats but also to relapse. That is, following a withdrawal During this period of abstinence, groups of rats differed period, the presence of these cues promotes renewed self- with respect to the extent of their exposure to ethanol- administration of opiates, cocaine, and ethanol. Similarly, associated cues. Finally, during a reacquisition test, rats former heroin addicts display physiological signs of nar- were permitted to again respond for the sweetened ethanol cotic withdrawal when they perform the "cooking up" ritual solution to evaluate the effect of the various extinction while being monitored by a polygraph or when presented treatments on relapse to ethanol self-administration. For with pictures containing drug-related cues. Alcoholics and example, in one experiment (Experiment 2), rats were ab- cigarette smokers similarly respond to the appropriate drug- stinent from ethanol for 12 days following the self-admin- associated cues with withdrawal symptoms and craving (see istration phase. Four independent groups of rats differed in reviews by Carter & Tiffany, 1999; Siegel, 1999a).
their treatment during this 12-day period. Rats in one group Epidemiological studies have evaluated relapse in treated were not exposed to ethanol-associated cues—they stayed drug users who have relocated to an environment very in their home cage throughout the abstinence phase of the different than that in which they used drugs (e.g., returning experiment (the home-cage group). Rats in the remaining Vietnam veterans who were addicted to heroin while in three groups differed in the number of ethanol-associated Vietnam or treated civilian drug addicts who moved to a cues presented during the abstinence. Rats assigned to the new environment following treatment). Compared with no-bar group received daily exposure to the operant cham- groups that have returned to environments rich in drug- ber, but there was no response lever in the chamber. Rats associated cues, relocated patients generally show far less assigned to the no-sacch group received daily sessions in the relapse (see review by Siegel, 1999a).
operant chamber, with the lever in place, but lever presses An implication of the conditioning analysis is that suc- had no consequence. Rats assigned to the sacch group also cessful treatment of drug addiction should acknowledge the received daily sessions in the operant chamber, but lever substantial inﬂuence of drug-predictive cues. On the basis of presses were reinforced with unadulterated saccharin solu- this reasoning, abstinence is most likely if the addict (who tion (no ethanol).
is not likely to relocate after therapy) is treated with a The results of the reacquisition test session for all groups protocol that incorporates extinction of the association be- in the Krank and Wall (1990, Experiment 2) study are tween these cues and the drug: "These treatments reﬂect a summarized in Figure 3. As can be seen in Figure 3 (and as logical extension of classical conditioning theory. If ad- conﬁrmed by the results of inferential statistical analyses), dicts' responses to drug-related stimuli reﬂect CRs, then cue exposure during extinction reduced self-administration for ethanol during reacquisition. Following abstinence, et al., 1993; McLellan, Childress, Ehrman, O'Brien, & sacch group rats responded less than did no-sacch group Pashko, 1986), effective with some drugs but not others rats, who, in turn, responded less than did no-bar group rats.
(e.g., Drummond, Tiffany, Glautier, & Remington, 1995), There was no statistically signiﬁcant difference between the effective only as adjunct to more traditional treatments (e.g., no-bar and home-cage groups.
Monti & O'Leary, 1999; Monti & Rohsenow, 1999; Roh- In sum, in this Krank and Wall (1990) research, relapse to senow, Monti, & Abrams, 1995), and effective with some ethanol self-administration was attenuated by exposure to clients and not with others (e.g., Powell et al., 1993; Rees & drug-associated cues during abstinence, with the extent of Heather, 1995). As recently summarized by Carroll (1999), relapse inversely related to the number of such cues pre- "while cue exposure approaches have generally been asso- sented during the extinction phase: "This suggests that ciated with reductions in some conditioned responses, the implementing some form of cue exposure to the patient's value of these procedures in producing clinically meaning- usual drinking environment during abstinence may be use- ful reductions in substance use has been met with only ful therapy" (Krank & Wall, 1990, p. 732).
modest success to date" (p. 261).
The Effectiveness of Cue Exposure Treatment for Why Cue Exposure Treatment May Not Be Effective Drug Addiction in Humans Findings indicating that cue exposure treatment may not There are several reviews of the literature concerning the always be an effective treatment strategy are explicable on effectiveness of cue exposure treatment for excessive use of the basis of laboratory work concerning extinction in gen- both licit and illicit drugs by humans: alcohol (e.g., Drum- eral, and extinction of conditional pharmacological re- mond & Glautier, 1994; Monti et al., 1993), nicotine (e.g., sponses in particular. The results of this research suggest Brandon, Piasecki, Quinn, & Baker, 1995), cocaine (e.g., strategies to maximize the effectiveness of cue exposure O'Brien, Childress, McLellan, & Ehrman, 1990), and opi- ates (e.g., Childress et al., 1986). The various studies haveused a variety of outcome measures (latency to relapse, Interoceptive Drug-Associated Cues extent of relapse, cue reactivity, self-reports of drug use andurges, and withdrawal symptoms). Although there are re- As indicated previously, interoceptive, as well as extero- ports that cue exposure treatment is effective (e.g., Drum- ceptive predrug cues may serve as CSs. Thus, the uncondi- mond & Glautier, 1994; Heather & Bradley, 1990; Monti et tional effects of a drug may be signaled by at least two CSs: al., 1993), the ﬁndings are mixed. That is, there also are (a) exteroceptive cues present at the time of drug adminis- reports that such treatments are ineffective (e.g., Dawe tration, and (b) interoceptive cues provided by the early Mean bar pressing for oral saccharin– ethanol reinforcement during the postabstinence reacquisition phase of the Krank and Wall (1990, Experiment 2) study. Prior to this test, rats weretrained to respond for the sweetened ethanol mixture. They subsequently were denied access toethanol. During this abstinence phase, independent groups of rats were not exposed to ethanolassociated cues (home-cage group); received daily sessions in which they were placed in theself-administration chamber, but the bar was not available (no-bar group); received daily sessionsin the operant chamber with the lever in place, but lever presses had no consequence (no-sacchgroup); or received daily sessions in the operant chamber with the lever in place and lever pressesreinforced with unadulterated saccharin solution (sacch group). From "Cue Exposure During aPeriod of Abstinence Reduces the Resumption of Operant Behavior for Oral Ethanol Reinforce-ment," by M. D. Krank and A.-M. Wall, 1990, Behavioral Neuroscience, 104, p. 730. Copyright1990 by the American Psychological Association. Reprinted with permission of the author.
SPECIAL ISSUE: APPLYING LABORATORY RESEARCH effects of the drug (DOCs) or the act of self-administration There is evidence that withdrawal symptoms and craving (SACs). That is, drug effects may often be signaled by can be directly elicited by a small dose of the drug to which compound predrug cues. There are several compound con- an individual is addicted. Schachter (1977) reported that ditioning phenomena that may be important for understand- some heavy smokers given low-nicotine cigarettes failed to ing the relationship between conditional drug effects and regulate their nicotine intake (i.e., increase the number of addictive phenomena, but one that is especially relevant is cigarettes smoked). These smokers, who repeatedly self- administered lower than normal doses of nicotine, reported Overshadowing, ﬁrst described by Pavlov (1927, pp.
extreme withdrawal distress. Other heavy smokers, who 142–143 and 269 –270), was extensively investigated by increased consumption when given low-nicotine cigarettes, Kamin (1969). Overshadowing is seen if two CSs simulta- effectively maintaining their normal nicotine intake, re- neously signal a UCS, and one CS is more salient than the ported no withdrawal distress. In experiments with rats, other. Other things being equal, a subject trained with a McDonald (2001) demonstrated the contribution of DOCs more salient CS will learn more rapidly than a subject to withdrawal symptoms. He found that rats with a history trained with a less salient CS. For example, if CS and CS of administration of large morphine doses (e.g., 50 mg/kg) are both effective CSs, but subjects learn a CS 3 UCS displayed behavioral and thermic evidence of morphine association faster than a CS 3 UCS association, CS is withdrawal when administered small doses (e.g., 5 mg/kg) said to be more salient than CS . When a compound CS of the opiate.
signals a UCS, subjects learn about the more salient CS at Cue exposure treatments sometimes may be ineffective the expense of the less salient CS. Consider the situation in because there is no attempt to extinguish these highly salient which CS and CS simultaneously signal a UCS. If CS is DOCs. As indicated by Cepeda-Benito and Short (1997), if more salient than CS , CS will become strongly associated the early effect of a drug is one cue that elicits CCRs, it is with the UCS, and little associative strength will develop possible that mere exposure to predrug environmental cues between CS and the UCS. It is said that CS overshadows may not effectively extinguish the association between pre- drug cues and the drug effect. Rather, "the inclusion of Overshadowing should be a characteristic of Pavlovian small drug doses during cue exposure treatments may better conditioning with pharmacological UCSs, just as it is with reproduce the CSs responsible for craving" (Cepeda-Benito nonpharmacological UCSs. Indeed, there is considerable & Short, 1997, p. 239). Indeed, some investigators de- evidence that overshadowing is a feature of learning about scribed successful cue exposure treatment procedures for drug effects (Dafters & Bach, 1985; Walter & Riccio, problem drinking that incorporate priming doses of alcohol 1983). Thus, drug tolerance may be controlled largely by (e.g., Sitharthan, Sitharthan, Hough, & Kavanagh, 1997).
DOCs or SACs (rather than simultaneously present, drug- Self-administration cues, drug addiction, and cue expo- paired environmental cues) because these interoceptive cues sure therapy. Recognition that SACs function as highly are more salient than the environmental cues (Kim et al., salient predrug cues also may have important implications 1999; Sokolowska, Siegel, & Kim, in press; Weise-Kelly & for cue exposure treatments. Typically, cue exposure treat- Siegel, 2001).
ment involves passive exposure of drug-associated environ- Drug-onset cues, drug addiction, and cue exposure treat- mental cues to patients who have self-administered drugs It is well established that relapse to drug use some- (e.g., Dawe et al., 1993). If SACs are among the cues that times is precipitated by exposure to small drug doses. Al- elicit CCRs, it is possible that effective extinction treat- though there are various interpretations of such priming ments should incorporate opportunities for the patient to effects (Shaham, Rodaros, & Stewart, 1994), it is possible engage in the behaviors that previously had culminated in that intraadministration associations may be responsible for drug administration. Recall that in the Krank and Wall some instances of the phenomenon (Siegel et al., 2000). For (1990) experiment with rats that had been trained to self- example, frequently it has been reported that a small dose of administer ethanol, the effective cue exposure treatments alcohol will augment the craving for additional alcohol and were those that involved components of the self-adminis- enhance subsequent alcohol consumption (see Goddard, tration response. That is, treatment was more effective for 1999; Siegel, 1987). This "loss of control" is incorporated in rats that had experience in making the response that previ- the doctrine of Alcoholics Anonymous: ously resulted in ethanol access but now resulted either inno programmed consequence or access to a dealcoholized Once he takes any alcohol into his system, something hap-pens, both in the bodily and mental sense, which makes it solution. Toben˜a et al. (1993) similarly suggested that the virtually impossible for him to stop. The experience of any effectiveness of cue exposure may be enhanced if it incor- alcoholic will conﬁrm that. . We are without defense porated self-administration behaviors: against the ﬁrst drink. (Anonymous, 1939, pp. 34 –35) It can also be useful to consider the possibility that controlling The insalubrious effect of the ﬁrst drink may be due to the for the direct consequences of self-administration of drugs alcoholic's association of that initial effect of alcohol (i.e., (e.g., drinking or injecting), could affect the extinction of the DOCs experienced soon after ingestion of alcohol) with affective states induced by drugs or drug cues . . treatment subsequent larger amounts of the drug: "The signal value of should incorporate speciﬁc strategies for dealing with thebehavioral chains involved in drinking, inhaling, smoking or a small drug dose may make a contribution to ‘binge' self-injecting drugs. The corresponding prediction would be drinking and drug ‘priming' effects in humans" (Goddard, that the practice of such behavioral rituals while the patients 1999, p. 418).
are exposed to cues (but without actual intake of drugs), would lead to faster extinction and loss of the signal value of parsimoniously analyze the situation in terms of an associa- such behaviors as cues for the drugs. This hypothesis may be tive process. If stress has been reliably associated with abu- worth investigating. (p. 215) sive drinking for a particular individual, then stress can func-tion as a conditional stimulus for the elicitation of compen- More recently, in discussing cue exposure therapy for satory responses and craving. . The extinction of stress as cigarette smoking, Brandon et al. (1995) also speculated a conditional cue for drug effects should occur just as the about a role for incorporating SACs in treatment and indi- extinction of a distinctive environment for drug effects oc- cated that more research is needed: "The beneﬁts of includ- curs. (pp. 209 –210) ing the self-administration ritual per se as part of a cue exposure treatment have not yet been empirically investi-gated" (p. 219, italics in original).
When a CR is extinguished, it typically reappears after a period of time. The phenomenon was ﬁrst noted by Pavlov: Images, Memories, and Emotions "Left to themselves, extinguished conditioned reﬂexesspontaneously recover their full strength after a longer or Laboratory research relevant to increasing the effective- shorter interval of time" (Pavlov, 1927, p. 58). Spontaneous ness of cue exposure discussed thus far primarily has been recovery of an extinguished response is well established and concerned with work using nonhuman animals. The ﬁnd- has been given extensive theoretical treatment (e.g., Brooks ings, however, are relevant to cue exposure therapy with & Bouton, 1993; Robbins, 1990).
humans. For example, the fact that effective CSs may be In common with other CRs, the CCRs that mediate drug "private" (such as DOCs and SACs), as well as "public" tolerance and withdrawal display spontaneous recovery. For (such as the environment of drug administration), although example, Brooks, Karamanlian, and Foster (2001) demon- primarily based on the results of research with rats, has strated that although ethanol tolerance can be extinguished important implications for the design of effective extinc- by repeated presentation of drug-associated cues, the toler- tion-based treatment procedures. However, there are some ant response reappears after a "rest" interval. This sponta- private predrug cues that can be studied only in humans.
neous recovery complicates attempts to effect long-term These include imagery of drug-paired stimuli and mood extinction of these CCRs during cue exposure therapy. With few exceptions (e.g., Corty & Coon, 1995; Hammersley, Images and memories. Merely thinking about their pre- 1992), however, spontaneous recovery generally has not ferred drug elicits withdrawal distress and craving in ciga- been recognized as a problem for cue exposure treatment. It rette smokers (e.g., Drobes & Tiffany, 1997), alcoholics would appear that, to be successful, cue exposure treatment (e.g., Weinstein, Lingford-Hughes, Martinez-Raga, & Mar- should use widely spaced extinction trials (that may mini- shall, 1998), and heroin addicts (e.g., Bradley & Moorey, mize the magnitude of spontaneous recovery; see Mackin- 1988). This imagery-elicited responding may be manifest tosh, 1974, pp. 421– 422). In addition, the cue exposure not only by subjective reports but also by activation of protocol should include postextinction sessions in which the distinctive brain circuits as revealed by positron emission spontaneously recovered pharmacological CCR may be re- tomography imaging techniques (e.g., Weinstein, Feldt- keller, et al., 1998). As summarized by Greeley and Ryan(1995), "A good case exists, then, for making cognitions per Context Effects se a pivotal concern of conditioning models, allowing thepossibility of cognitions as interoceptive cues" (p. 132, The fact that extinguished CRs display spontaneous re- italics in original). Research concerning the incorporation of covery suggests that extinction does not abolish the ability such private stimuli into cue exposure procedures (e.g., of a CS to elicit conditional responding. Nevertheless, a Kominars, 1997) will inﬂuence in an important way this view of extinction as unlearning—an eradication of the form of behavioral therapy for addiction.
association formed during acquisition—is pervasive and is Emotions, especially negative emotions, are implicit in most implementations of cue exposure therapy.
frequent elicitors of withdrawal distress and craving. For Results of research conducted in the past 20 years, however, example, Ludwig and Stark (1974) reported that over 75% indicate that extinction does not entail the loss of prior of their sample of patients experienced craving for alcohol learning. An extensive series of experiments, primarily by when "depressed," "nervous," or "under stress." Similarly, Mark Bouton and colleagues (e.g., Bouton, 1994, 2000; Mathew, Claghorn, and Largen (1979) found that about Bouton & Swartzentruber, 1991), indicate that, just as 85% of their patients reported that "non-alcohol-related something is learned during acquisition (the CS–UCS asso- events of an unpleasant nature" (p. 605) precipitated crav- ciation), something also is learned during extinction (a ing. Similar results have been found with heroin addicts (see CS–no-UCS association). During extinction, the association summary by Greeley & Ryan, 1995). There are various learned during acquisition remains intact, while the new, interpretations of the contribution of negative emotional conﬂicting association is acquired: "The signal winds up states to withdrawal distress (Stewart, 2000); however, as with two available ‘meanings.' It is ambiguous . . its discussed by Poulos, Hinson, and Siegel (1981), Pavlovian current meaning— or the behavior it currently evokes—is conditioning may be a factor: determined by the current context" (Bouton, 2000, p. 57).
While one can plausibly relate the psychodynamics of stress This view of extinction has profound implications for cue and depression to drug use, the conditioning analysis can exposure therapy.
SPECIAL ISSUE: APPLYING LABORATORY RESEARCH A phenomenon termed renewal (Bouton, both rats and humans, Bouton (2000) suggested several 1993) provides evidence for the survival of CRs, even procedures for enhancing the effectiveness of cue exposure.
following extensive extinction. Renewal is seen if a CR is For example, renewal is reduced if cues present during established in one context (Context ) by repeated CS– extinction are presented again on the test of renewal (e.g., UCS pairings and subsequently extinguished in a different Brooks & Bouton, 1994): "The ﬁndings begin to suggest ) by repeated CS-alone presentations.
that building retrieval cues or retrieval opportunities into the Despite the fact that following extinction, there is no con- period after therapy—perhaps through reminder cards or ditional responding in Context , when the subject is pre- reminder telephone calls from the therapist—will help pre- sented with the CS in Context the CS again elicits CRs; vent relapse and extend behavior change" (Bouton, 2000, p.
that is, conditional responding is renewed. Renewal has been seen in many different types of conditioning prepara- Another procedure to increase the long-term effective- tions, with both nonhuman animals and humans. In exper- ness of extinction is to conduct extinction, to the extent iments with rats, Context possible, in Context . For example, Blakey and Baker sist of experimental chambers that are distinguished by (1980) described such a cue exposure treatment of a prob- olfactory, visual, and auditory cues but may also consist of lem drinker. The patient, and one or two therapists, would different hormonal, drug, or deprivation states. In experi- sit in the pub (where the patient habitually drank) and drink ments with humans, contexts may be provided by experi- only soft drinks.
mentally induced moods (e.g., Eich, 1995). Although re- Drug use is part of Context , thus extinction therapy newal typically has been demonstrated by presenting the CS may be more effective if it actually incorporated some following extinction in Context drug use. Bouton (2000) provided an example of such a evidence, from research with rats, that renewal may be seen procedure that could be used with a cigarette smoker. Dur- when the CS again is presented in a third, neutral context.
ing cue exposure, the patient not only would be presented As summarized by Bouton and Swartzentruber (1991), with cigarette-associated cues but also would smoke afew cigarettes, thereby increasing the similarity between The loss of responding during extinction depends to someextent on the subject learning about, and suppressing perfor- mance in, the extinction context. One could similarly expect Because those trials would initially reintroduce a contextual that the positive effects of exposure therapy could be speciﬁc cue connected with smoking, they may slow down behavior to the therapy context. It is as if extinction depends inherently change in the short run. However, in the long run, because on the subject learning about some version of the idea, ‘the they would allow more effective extinction of some of the CS is safe here.' (p. 126, italics in original) cues stimulating relapse, controlled exposures to occasional Bouton (2000) provided an example of the potential of lapses could theoretically facilitate a more permanent changein behavior. (p. 60) the renewal effect to stymie the intentions of the cue expo-sure therapist. Consider the case of the cigarette smoker Finally, there is theoretical and empirical support for the who habitually smokes in particular contexts (e.g., at work idea that conducting extinction in a variety of different or under the inﬂuence of alcohol). Thus, a variety of ex- contexts will decrease renewal. By presenting the CS alone teroceptive and interoceptive cues (including the act of not in a single Context , but also in many other contexts, smoking and the effects of nicotine and other tobacco con- the likelihood of shared features between the context of stituents) provide a context in which smoking typically extinction and the context of acquisition is increased (Bou- occurs. Following cue exposure in the clinic, this individual ton, 2000). Thus, cue exposure may be more effective if it may no longer experience substantial withdrawal symptoms is conducted in many different contexts (rather than, for or craving when confronted by cigarette-associated stimuli example, only in the clinic).
(e.g., the sight of a cigarette or the sight of someone smok-ing). However, when this individual again returns to Con- Occasion Setting (the workplace or the internal state induced by alcohol), cigarette-associated stimuli will again elicit CCRs.
Cue exposure treatment is designed to extinguish learned Moreover, if renewed smoking occurs in this context (thus responses elicited by drug-paired cues. However, results of reexposing the individual to contextual cues resulting from recent Pavlovian conditioning research suggest that re- smoking), the renewal effect is further enhanced: peated presentations of stimuli that had been paired withthe UCS do not inevitably lead to extinction. This research In this manner the initial lapse produced by renewal orspontaneous recovery will introduce additional contextual has concerned a phenomenon variously termed facilitation cues that further trap the smoker into smoking again. One (Rescorla, 1986), modulation (Swartzentruber, 1995), or— begins to envision an ever-expanding set of contextual cues.
the term used here—occasion setting (Holland, 1992).
In this way, a slip or lapse may spiral into relapse. (Bouton, What is occasion setting? Renewal provides one dem- onstration of the importance of contextual cues in extinction Implications of the renewal effect for cue exposure ther- of a CS–UCS association. Another (perhaps related) exam- Cue exposure will be successful, in the long term, to ple is provided by occasion setting. The relationship be- the extent that the therapy decreases renewal and promotes tween a CS and a UCS may be termed a binary relation retrieval of the extinction learning when the patient returns (Domjan, 1998, p. 244). Both humans and nonhuman ani- . On the basis of the results of research with mals can learn that a third stimulus—an occasion setter— provides information that a binary relationship will be in these target cues and the drug effect. Attempting to extin- effect (Hardwick & Lipp, 2000; Schmajuk & Holland, guish only the occasion setter (e.g., having the patient 1998). This third stimulus is the occasion setter.
repeatedly visualize cues that occur well before drug self- Occasion setting is a phenomenon of compound condi- administration) would be fruitless.
tioning. As previously discussed, the CS that signals a drugoften may be conceptualized as a compound CS consisting Pavlovian Conditioning and Pharmacological of several elements. In the examples given thus far, the Treatment of Withdrawal Symptoms various elements of the compound CS (e.g., pharmacolog-ical drug-onset cues and environmental cues) occur at ap- Cue exposure therapy is designed to decrease the mag- proximately the same time. This may be termed a simulta- nitude of abstinence symptoms elicited by drug-associated neous compound. In contrast, one element of the compound stimuli. On the basis of a conditioning interpretation, these may occur some time before the second element. Using the symptoms are CCRs, and cue exposure is an extinction usual terminology for such serial compounds, the ﬁrst ele- procedure. An alternative strategy for decreasing the ment is termed the occasion setter, and the second element strength of CCRs is to interfere with the biological bases of is termed the target.
their expression (see Koob, 2000). Results of some recent Research using serial compounds indicates that the occa- research have addressed the intracellular and intercellular sion setter, in contrast with the target, does not enter into a processes engaged by cues that have been associated with direct association with the UCS—that is, it does not func- drug administration (see Siegel et al., 2000).
tion as a CS. Rather, it acquires unique properties. Asdiscussed by several investigators (e.g., Anagnostaras & Conditional Intracellular Alterations Robinson, 1996; Greeley & Ryan, 1995), a complete anal-ysis of the contribution of learning to drug effects should The structural changes in the central nervous system that acknowledge the acquisition of occasion-setting properties are responsible for learning and drug effects require gene of drug-paired feature cues, as well as the acquisition of activation. The gene that encodes a transcription factor, conditional responding by drug-paired target cues.
c-fos, has been implicated in learning and drug tolerance What is special about occasion setting? (Nye & Nestler, 1996; Sotty, Sandner, & Gosselin, 1996).
learn about occasion setters, just as they learn about CSs; That is, c-Fos (especially striatial c-Fos) mediates the action however, the content of learning about occasion setters is of many common drugs of abuse (e.g., Hope, Kosofsky, unique. For example, although repeated presentations of a Hyman, & Nestler, 1992; Liu, Nickolenko, & Sharp, 1994), CS by itself (in the absence of the UCS) leads to extinction and c-Fos also is important for memory consolidation (Sotty of conditional responding, such extinction is not character- et al., 1996). There is evidence that conditional drug effects istic of occasion setting. That is, repeated presentations of are seen in conjunction with conditional c-Fos expression an occasion setter by itself does not lead to any diminution (Baptista et al., 1998; Thiele, Roitman, & Bernstein, 1998).
in the occasion-setting properties of the stimulus. Following For example, Baptista et al. (1998) used the paired– un- such attempted extinction, the organism still responds to the paired situational-speciﬁcity design of Siegel et al. (1978), target CS with conditional responding if this CS is preceded described previously, to simultaneously evaluate both tol- by the occasion setter. Although the nonextinguishability of erance to the analgesic effect of morphine and striatal c-Fos an occasion setter has been demonstrated primarily with the levels. They reported that rats not only showed behavioral traditional stimuli used in Pavlovian conditioning (e.g., Hol- evidence of situational-speciﬁcity of tolerance (i.e., paired land, 1992; Ross & Holland, 1981), it also has been dem- morphine rats were more tolerant to the analgesic effect of onstrated with drugs as UCSs (Ramos, Siegel, & Bueno, in morphine than were unpaired morphine rats) but also dem- press). As suggested by Ramos et al., the fact that some onstrated situational-speciﬁcity of c-Fos expression (i.e., drug-paired stimuli may function as occasion setters, rather paired morphine rats displayed higher striatal c-Fos levels than as CSs, has important implications for cue exposure than did unpaired morphine rats). More recently, Schroeder, Holahan, Landry, and Kelly (2000) also demonstrated con- Implications of occasion setting for cue exposure ther- ditional changes in fos expression following training with Sometimes, when cue exposure therapy is ineffec- morphine. In addition, Thiele et al. (1998) reported similar tive, it is possible that the therapist attempted to extinguish ﬁndings with respect to ethanol.
an occasion setter, rather than a CS. As indicated, repeated The c-Fos protein combines with other proteins to form presentations of an occasion setter by itself does not atten- an activator protein 1 complex—AP-1 (Angel et al., 1998; uate its occasion-setting properties. Consider, for example, Bohmann et al., 1987). This AP-1 complex binds to, and the sequence of events likely to occur for a heroin addict.
activates, genes. Baptista et al. (1998) demonstrated that Many cues provided by the rituals involved in procuring the AP-1 binding was increased more in the striatum of paired drug and injection paraphernalia occur well before the ac- morphine rats than in the striatum of unpaired morphine tual heroin injection. It is possible that the cues immediately preceding the central effects of heroin (e.g., piercing the In sum, stimuli present at the time of drug administration skin with the hypodermic needle, DOCs, SACs) are the modify not only the expression of tolerance but also the functional CSs—the target cues. The more distal cues are molecular changes hypothesized to mediate tolerance. In- occasion setters that signal the binary relationship between creasing understanding of the molecular bases of condi- SPECIAL ISSUE: APPLYING LABORATORY RESEARCH tional pharmacological responses may lead to the develop- Indeed, several investigators have reported that such antag- ment of drugs that modulate these intracellular functions onist treatment prevents the developments of morphine tol- that contribute to drug addiction and relapse.
erance (e.g., Kellstein & Mayer, 1991) and attenuates theexpression of established morphine tolerance (e.g., Hoff- Conditional Intercellular Alterations mann & Wiesenfeld-Hallin, 1994; Kim & Siegel, 2001). Ifsuch enhancement of CCK activity is conditionally elicited Another strategy for pharmacological treatment of addic- by morphine-paired cues, the CCR usually elicited by these tion is to use a drug that modulates the conditional changes cues should be attenuated by pretreating rats with a CCK in neurotransmitter activity that mediate the behavioral ex- antagonist prior to the presentation of these cues. This pression of CCRs. There recently has been progress delin- ﬁnding recently has been reported by Kim and Siegel eating such changes with respect to ethanol and opiates. For (2001). They demonstrated that, in rats with a history of example, on the basis of results of microdialysis studies, morphine administration, a hyperalgesic CCR is apparent in Quertemont, de Neuville, and De Witte (1998) suggested rats presented with drug-associated cues (and pretreated that the CCRs elicited by ethanol-paired cues are mediatedby conditional release of the neuromodulator, taurine, in the with an inert substance), but no such CCR is apparent in rats tested following pretreatment with a CCK antagonist.
An especially promising area of research concerns the On the basis of a Pavlovian conditioning interpretation, development of pharmacotherapies for addiction that inter- the CCRs that mediate tolerance (when the drug is admin- fere with neurotransmitter activities that occur in anticipa- istered) are expressed as withdrawal symptoms (when the tion of opiates. There are ﬁndings suggesting that adminis- usual predrug cues are not followed by the usual pharma- tration of opiates elicits an increase in the production or cological consequences). Thus, it would be expected that synthesis of anti-opioid peptides (AOPs). An AOP, as the these associatively mediated withdrawal symptoms should term indicates, counteracts the effects of opiates and con- be attenuated by pretreatment with a CCK antagonist. Lu tributes to tolerance and withdrawal symptoms (Wiesen- et al. (2000) reported that the expression of withdrawal feld-Hallin, Lucas, Alster, Xu, & Ho¨kfelt, 1999). Increases symptoms in rats with a history of morphine administration in AOP activity may occur not only unconditionally (in was suppressed by pretreatment with a CCK antagonist, response to the presence of the drug) but also conditionally but these investigators did not evaluate the contribution of (in response to predrug cues); thus, interfering with AOP predrug cues to these withdrawal symptoms. Further re- activity may decrease CCRs elicited by drug-associated search can determine whether withdrawal symptoms, seen stimuli (Kim & Siegel, 2001).
when the long-abstinent organism again is confronted withdrug-associated cues (see Carter & Tiffany, 1999; Siegel, CCK as an AOP 1999a) are attenuated by a CCK antagonist (as would be expected if such symptoms are CCRs mediated by CCK Although several putative AOPs have been proposed, one that has received considerable attention is CCK. There isevidence that CCK attenuates the effect of morphine. Forexample, if CCK is administered exogenously, it blocks morphine-induced analgesia in a dose-dependent manner(e.g., Han, 1995; Mitchell, Lowe, & Fields, 1998). Co- Inasmuch as there is evidence that the CCRs elicited by treatment with a CCK receptor antagonist prevents CCK predrug cues are mediated by a conditional increase in from attenuating opioid effects (Suh, Kim, Choi, & Song, activity (Kim & Siegel, 2001), the compensatory 1995). Blocking CCK receptors potentiates morphine anal- conditioning analysis of tolerance and withdrawal provides gesia in rats (e.g., Zhou, Sun, Zhang, & Han, 1992) and a rationale for the use of a CCK antagonist as a potential humans (e.g., McCleane, 1998). Moreover, morphine ad- addiction treatment. Many other pharmacotherapies for ad- ministration accelerates the release of CCK from the central diction have been proposed, on the basis of alternative nervous system in a dose-dependent manner (Zhou et al., theoretical analyses of addiction, and some have achieved 1992). Two subtypes of CCK receptors have been identiﬁed widespread acceptance. There now are a variety of drugs and termed CCK and CCK , in reference to the relative designed to decrease craving to modify the neurochemical distribution of the receptors in alimentary and brain tissue(Saito, Sankaran, Goldine, & Williams, 1980). The avail- bases of substance abuse. In addition, there are drug treat- ability of highly selective receptor antagonists has demon- ments that use agonists, others that use antagonists, and strated that the anti-opioid function of CCK is active at the others that use mixed agonist–antagonists (for a review of CCK , rather than at the CCK receptor site (Wiesenfeld- addiction pharmacotherapy, see Gottschalk, Jacobsen, & Hallin et al., 1999).
Kosten, 1999). The use of a CCK antagonist is but one potential strategy designed to meet a pressing need in opioidaddiction treatment: "The main challenge in the manage- CCK, Tolerance, and Withdrawal Symptoms ment of opioid addiction is to develop a pharmacotherapy to If tolerance were mediated by enhanced CCK activity, decrease the protracted opioid abstinence syndrome" (Lu et CCK antagonists would be expected to attenuate tolerance.
al., 2000, p. 832).
Summary and Conclusions Cue exposure therapy is a behavioral treatment for the attenuation of the drug-compensatory responding. Results It has been known for a long time that the effects of a of recent research, with rats, suggest a neurochemical basis drug are importantly modulated by responses elicited by for such responding: "Conditional compensatory respond- drug-paired cues. The ﬁnding has been reported by clini- ing elicited by morphine-onset cues is mediated by a con- cians (e.g., Macnish, 1859), epidemiologists (e.g., Fryk- ditional enhancement in CCK activity" (Kim & Siegel, holm, 1979), and laboratory scientists (e.g., Deffner-Rap- 2001, p. 708). Such ﬁndings provide a basis for a potential pold, Azorlosa, & Baker, 1996). It features in narrative pharmacotherapy for opiate addiction— blocking the effect reports of addicts (e.g., Biernacki, 1986) and in novels of such enhanced CCK activity with a CCK antagonist (see describing opiate effects (see Siegel, 1983). The contribu- Lu et al., 2000).
tion of drug-anticipatory responses to drug effects is seen in We have summarized evidence that compensatory re- many species, from snails (Kavaliers & Hirst, 1986) to sponses, unconditionally elicited by a drug, come to condi- humans (e.g., Remington, Roberts, & Glautier, 1997).
tionally be elicited by a variety of cues paired with the drug, These observations have led to the formulation of drug and we have discussed the clinical signiﬁcance of such administration as a Pavlovian conditioning trial. Uncondi- CCRs to addiction. It is not always the case, however, that tional compensatory responses, elicited by pharmacological pharmacological stimulation initiates compensatory re- stimulation, come to be elicited by drug-paired cues. These sponses. Depending on the mechanism of drug action, the cue-elicited CCRs mediate tolerance when the usual pre- UCRs to some drugs consist of responses that augment drug cues are followed by the usual drug effect and are (rather than attenuate) the pharmacological UCS. Although expressed as withdrawal symptoms when the usual predrug the reasons why some UCRs elicit augmentative (rather cues are not followed by the usual drug effect (see reviews than compensatory) responses is debatable (see Dworkin, by Siegel, 1999a; Siegel et al., 2000). Results of recent 1993; Eikelboom & Stewart, 1982; Ramsay & Woods, research concerning the interaction between pharmacology 1997), such UCRs result in noncompensatory CRs; that is, and conditioning have indicated that private interoceptive cues associated with augmentative UCRs will come to elicit cues (e.g., DOCs, SACs, imagery, and moods), as well as conditional augmentative responses (CARs), rather than public exteroceptive cues, may be associated with the drug CCRs. For example, following a series of amphetamine effect and elicit CCRs.
injections, amphetamine-associated cues elicit a CAR of The contribution of Pavlovian conditioning to phenom- amphetamine-like hyperactivity (e.g., Tilson & Rech, ena of addiction provides a focus for appreciating the ways 1973). Although CCRs progressively decrease the drug in which laboratory research (frequently conducted with effect over the course of repeated administrations, CARs nonhuman animals) and clinical observations are related. In progressively increase the drug effect over the course of this article we have discussed three areas of interest to both successive administrations. Such enhancement is termed the experimenter and the clinician indicating this relation- reverse tolerance, or sensitization, and CARs contribute to ship: (a) drug overdose, (b) cue exposure therapy, and (c) sensitization much as CCRs contribute to tolerance (e.g., pharmacological treatment of withdrawal symptoms.
Hinson & Poulos,1981; Siegel et al., 2000). Discussion of Heroin overdose is a major complication of heroin addic- the contribution of CARs in general, or drug sensitization in tion (Darke & Zador, 1996). In laboratory animals, in heroin particular, to drug addiction is beyond the scope of this addicts, and in patients receiving medically prescribed opi- review (but see Bardo & Bevins, 2000; Joseph, Young, & ates, an overdose may result when the drug is administered Gray, 1996; Robinson & Berridge, 2001; Siegel, 2002; in the absence of the usual predrug cues. In these circum- Silverman & Bonate, 1997).
stances, the CCRs that mediate tolerance are not expressed, Both researchers and clinicians want to understand ad- and overdose may be conceptualized as a failure of toler- diction and develop effective treatment strategies. Although ance to occur.
drug addiction is a major health problem, it also is a fasci- Whereas CCRs mediate tolerance when the drug is ad- nating phenomenon. Why do people self-administer fer- ministered, their expression in the absence of the drug mented fruit, the products of intoxicating plants, or syn- results in uncomfortable symptoms, craving, and an in- thetic (and more potent) versions of such chemicals? "Seek- crease in the incentive value of the drug (Hutcheson, Ever- ing intoxication . . is paradoxical. It seemingly deﬁes the itt, Robbins, & Dickinson, 2001). Cue exposure therapy is logic of natural selection" (Courtwright, 2001, p. 91). The an attempt to extinguish these CCRs. On the basis of results paradox has captured the attention of researchers interested of laboratory research, the effectiveness of cue exposure in the behavioral, sociological, evolutionary, neurochemi- therapy should be enhanced if the therapist recognizes (a) cal, and molecular– biological bases of addiction (see Siegel that interoceptive as well as exteroceptive cues may have & Allan, 1998; Siegel et al., 2000). One would hope that become associated with the drug effect; (b) that spontaneous this extensive analysis of addiction would translate into recovery may occur; (c) that renewal of conditional re- improved treatment outcomes. In this article, we have elab- sponding may occur when, following cue exposure in a orated a single theoretical framework (Pavlovian condition- particular context, the patient is confronted with predrug ing of drug effects resulting in CCRs) and described how cues in a context other than that in which extinction oc- data and theory arising from research based on this analysis curred; and (d) that some predrug cues may function pri- suggest procedures to decrease drug overdoses and improve marily as occasion setters rather than as CSs.
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United States Court of Appeals for the Federal Circuit DAIICHI SANKYO COMPANY, LTD., AND DAIICHI SANKYO, INC., MATRIX LABORATORIES, LTD., MYLAN INC., MYLAN LABORATORIES, INC., AND MYLAN PHARMACEUTICALS, INC., Appeal from the United States District Court for the District of New Jersey in Case No. 06-CV-03462, Judge