Regulation of Drug Taking by Sensitization and Habituation.

Regulation of Drug Taking by Sensitization and Habituation

Frances K. McSweeneyWashington State University

Eric S. MurphyUniversity of Alaska Anchorage

Benjamin P. KowalWashington State University

The authors argue that drug taking is an operant behavior that is reinforced by the drug itself.The effectiveness of a drug as a reinforcer is modulated by sensitization and habituation tothe drug as it is consumed. According to this model, drug taking stops when habituationreduces the ability of the drug to reinforce its own consumption. Drug taking resumes whenspontaneous recovery restores the effectiveness of the drug as a reinforcer. This parsimoniousmodel provides a framework for understanding many findings in the drug literature, includingacute and chronic tolerance, the effect of deprivation on consumption, the contextualspecificity of tolerance, polydrug abuse, cross-sensitization between stress and drugs, behav-ioral sensitization, priming, and reinstatement. Although this model cannot explain all aspectsof drug taking (e.g., the effect of cognitive manipulations), it has many implications forunderstanding and controlling human drug consumption and addiction.

Keywords: drug reinforcers, sensitization, habituation, drug consumption, addiction

Drugs often serve as reinforcers (e.g., Schuster & Thomp-son, 1969; Weeks, 1962), and they are assumed to controlbehavior in the same manner as conventional reinforcers—for example, food and water (e.g., Di Chiara & North, 1992;Grigson, 2002; Koob, 1992; Nesse & Berridge, 1997; Wise,1982). Animals sensitize and then habituate to the sensoryproperties of conventional reinforcers with their repeateddelivery within an experimental session (e.g., McSweeney,Hinson, & Cannon, 1996). Sensitization is an increase inresponsiveness to a repeatedly presented stimulus during itsinitial presentations (e.g., Groves & Thompson, 1970).1

Habituation is a subsequent decrease in responsiveness to astimulus with its further presentation (e.g., Thompson &Spencer, 1966). Although habituation was once restricted toreflexive or unlearned behavior and to stimuli that lackbiological significance, more recent research shows thathabituation may be learned (e.g., Wagner, 1976), may occurfor complex behaviors (e.g., Poucet, Durup, & Thinus-Blanc, 1988), and may occur for biologically significantstimuli (e.g., food; Swithers & Hall, 1994). Therefore, ha-bituation may help to control operant behavior.

Figure 1 illustrates sensitization and habituation to re-peatedly presented reinforcers. The solid lines in Figure 1present results for the mean of four or five rats pressinglevers (top and bottom graphs) or pigeons pecking keys(middle graph) for food reinforcers during 60-min experi-mental sessions. The dotted line in the middle graph repre-sents the results for the mean of five alcohol-preferring rats(P rats; Li & Lumeng, 1984) pressing a lever for a 10%ethanol solution delivered on a variable interval 15-s sched-ule during 50-min sessions (Murphy, 2003). In each case,the programmed availability of reinforcement was constantacross the session.

In spite of constant reinforcement, rate of responding forfood increased (top graph), decreased (middle graph), orincreased and then decreased (bottom graph) within theexperimental session. Overall rate of reinforcement helps todetermine which of these patterns will be observed (e.g.,McSweeney, 1992). The decreasing pattern (middle graph)is usually observed when reinforcers are provided at highrates (e.g., 120 reinforcers per hour or more). The bitonic

1 Sensitization, as it is studied in the literature on sensitization–habituation, should be distinguished from behavioral sensitizationin the drug literature. Behavioral sensitization to drugs has beendefined in many ways, but it basically refers to an increase in theeffectiveness of a drug after its repeated administration (e.g.,Kalivas & Stewart, 1991). To distinguish between the two forms ofsensitization, we refer to the process in the literature on sensitiza-tion–habituation as sensitization. We refer to sensitization in thedrug literature as behavioral sensitization. Later in the article, weargue that sensitization from the literature on sensitization–hab-ituation contributes to behavioral sensitization in the drug litera-ture, but this is an empirical question that should not be obscuredby using the same term to describe both phenomena.

Frances K. McSweeney and Benjamin P. Kowal, Department ofPsychology, Washington State University; Eric S. Murphy, De-partment of Psychology, University of Alaska Anchorage.

Preparation of this article was partially supported by NationalInstitute of Mental Health Grant R01 MH61720. We thank Re-becca Craft and John M. Roll for their comments on an earlierversion of this article.

Correspondence concerning this article should be addressedto Frances K. McSweeney, Department of Psychology, Wash-ington State University, Pullman, WA 99164-4820. E-mail:[email protected]

Experimental and Clinical Psychopharmacology Copyright 2005 by the American Psychological Association2005, Vol. 13, No. 3, 163–184 1064-1297/05/$12.00 DOI: 10.1037/1064-1297.13.3.163

163

pattern (bottom graph) is usually observed when reinforcersare presented at intermediate rates (e.g., 60 reinforcers perhour). A relatively flat pattern (top graph) is observed whenreinforcers are delivered at low rates (e.g., fewer than 15reinforcers per hour). Within-session changes in respondinghave been reported often for both conventional (e.g., Mc-Sweeney & Roll, 1993) and drug (e.g., Meisch & Thomp-son, 1974; Murphy, 2003; Nowak, McKinzie, McBride, &Murphy, 1999; Weiss et al., 1992; Wise, Leone, Rivest, &Leeb, 1995) reinforcers.

The within-session changes in operant responding re-ported in Figure 1 are produced by changes in the ability ofthe reinforcer to support behavior with its repeated delivery,rather than by other factors (e.g., McSweeney, Weatherly, &Swindell, 1996; see McSweeney, Hinson, & Cannon, 1996,for a review). The changes in reinforcer effectiveness areproduced primarily by sensitization and habituation to thereinforcer with its repeated delivery. According to this ar-gument, presentation of a reinforcer generates both sensiti-zation and habituation. Rate of responding is determined bythe interaction of these processes. Within-session increasesin responding (see Figure 1, top graph) are observed whensensitization dominates habituation. Within-session de-creases in responding (see Figure 1, middle graph) areobserved when habituation dominates sensitization. Bitonicpatterns of responding (see Figure 1, bottom graph) occurwhen sensitization dominates early and habituation domi-nates later.

Habituation provides a more accurate and precise char-acterization of the declines in reinforcer effectiveness thanthe alternative of satiation (McSweeney & Murphy, 2000;McSweeney & Roll, 1998). We define satiation as thosewho have studied it have defined it. That is, satiation refersto a decrease in the consumption of an ingestive stimulus(e.g., food, water) as it is repeatedly consumed (i.e., withrepeated sips or bites; e.g., Strubbe & van Dijk, 2002). Thefactors that contribute to satiation are called satiety factors(e.g., Mook, 1996). Early research on satiety focused on thecontribution of postingestive factors (e.g., stomach disten-sion, blood sugar levels). Recent satiety research shows thathabituation to the sensory properties of food (e.g., a de-crease in responsiveness to taste) contributes to satiation(e.g., Swithers & Hall, 1994). That is, habituation is oneamong many satiety factors.

dotted line in the middle graph represents the results when alcohol-preferring rats pressed a lever for a 10% ethanol solution during50-min sessions. The results for food were derived from “Sensi-tization–Habituation May Occur During Operant Conditioning,”by F. K. McSweeney, J. M. Hinson, and C. B. Cannon (1996),Psychological Bulletin, 120, p. 257. The results for ethanol werederived from “Dynamic Changes in the Value of Ethanol Rein-forcers,” by E. S. Murphy (2003), unpublished doctoral disserta-tion, Washington State University, Pullman. The same scale isused on the ordinate for the increasing (top graph) and bitonic(bottom graph) functions. A larger scale was needed in the middlegraph to illustrate the decreasing function.

Figure 1. Examples of within-session patterns of operant re-sponding. The figure presents the proportion of total-session re-sponses emitted during successive 5-min intervals in an experi-mental session. The solid line represents the results when ratspressed levers (top and bottom graph) or pigeons pecked keys(middle graph) for food reinforcers during 60-min sessions. The

164 MCSWEENEY, MURPHY, AND KOWAL

Our reasons for questioning satiation as an explanationfor the dynamic changes in reinforcer effectiveness arepresented in the following studies: McSweeney and Roll(1998) and McSweeney and Murphy (2000). Most impor-tant, the empirical characteristics of within-session changesin responding are remarkably consistent with the character-istics of behavior undergoing sensitization and habituation(McSweeney, Hinson, & Cannon, 1996; McSweeney &Murphy, 2000; McSweeney & Roll, 1998). Thompson andSpencer (1966) listed nine properties of habituation andargued that these characteristics could serve as an opera-tional definition of that term. McSweeney and Murphy(2000) expanded the list to 14 properties on the basis ofmore recent research (see Table 1). To date, operant re-sponding for repeatedly presented conventional reinforcers(e.g., food, water) has shown 11 of 14 generally acceptedproperties of behavior undergoing sensitization andhabituation.

Some of these characteristics separate the role of habit-uation from the role of other satiety factors. For example,changing the reinforcer for a brief time late in the sessionincreases response rate after the original reinforcer is re-

stored (Aoyama & McSweeney, 2001; McSweeney & Roll,1998). Response rate increases regardless of whether thechange in reinforcer is an increase or a decrease in theamount of food delivered and regardless of whether thechange produces an increase or a decrease in response ratewhile it is in effect. Finding such “dishabituation” is con-sistent with habituation (Characteristic 4, Table 1) but notwith other satiety variables. Providing more food shoulddecrease, not increase, responding by producing more sati-ation (e.g., higher blood glucose levels, more stomach dis-tension; for more arguments, see McSweeney & Murphy,2000; McSweeney & Roll, 1998).

If our analysis is correct, then it may provide a simple andtestable model for the regulation of drug consumption. First,assume that drugs are consumed because they act as rein-forcers and, therefore, increase the frequency of any behav-ior that they follow, including their own consumption (e.g.,Schuster & Thompson, 1969; Weeks, 1962). Second, as-sume that animals sensitize and then habituate to drugreinforcers as consumption repeatedly exposes the animal tothe sensory properties of the drug (e.g., its taste, its subjec-tive effect). In that case, drug consumption might stop when

Table 1Some Empirical Characteristics of Habituation Adapted From McSweeney and Murphy’s 2000 Study

Characteristic Description

1. Spontaneous recoverya,b (e.g., Thompson &Spencer, 1966)

Responsiveness to a habituated stimulus recovers when that stimulus is notpresented for a time

2. Stimulus specificitya,b (e.g., Swithers &Hall, 1994; Whitlow, 1975)

Habituation is disrupted by changes in the presented stimulus

3. Variety effectsa,b (e.g., Broster & Rankin,1994)

Habituation occurs more slowly to stimuli that are presented in a variable,rather than a fixed, manner (e.g., after variable, rather than fixed,interstimulus intervals)

4. Dishabituationa,b (e.g., Thompson &Spencer, 1966)

Presenting a strong, different, or extra stimulus restores responsiveness to ahabituated stimulus

5. Dishabituation habituates (e.g., Thompson& Spencer, 1966)

Repeated presentation of dishabituators reduces their ability to restorehabituated responding

6. Stimulus ratea,b (e.g., Thompson &Spencer, 1966)

Faster rates of stimulus presentation yield faster and more pronouncedhabituation than slower rates

7. Stimulus rate and recovery (Staddon &Higa, 1996)

Spontaneous recovery may be faster after faster rates than after slower ratesof stimulus presentation.

8. Stimulus exposurea,b (e.g., Thompson &Spencer, 1966)

Responsiveness to a repeatedly-presented stimulus decreases with increases instimulus exposure.

9. Long-term habituationa,b (e.g., Wagner,1976)

Some habituation is learned and persists over the passage of time.

10. Repeated habituationsa (e.g., Thompson &Spencer, 1966)

Habituation may become more rapid with repeated habituations.

11. Stimulus intensitya (e.g., Thompson &Spencer, 1966)

Habituation is sometimes, but not always (e.g., Groves & Thompson, 1970),faster and more pronounced for less than for more intense stimuli

12. Generalitya,b (e.g., Thorpe, 1966) Habituation occurs for most, if not all, stimuli and species of animals. Theexact rate of habituation differs depending on the species, the stimulus, theresponse used as a measure, and the individual subject (e.g., Hinde, 1970).

Habituation is often accompanied by sensitization (e.g., Groves & Thompson,1970). Therefore, if habituation occurs, then Characteristics 13 and 14might also be observed.

13. Sensitization by initial stimuluspresentationsa,b (e.g., Groves & Thompson,1970)

An increase (sensitization), rather than a decrease (habituation), inresponsiveness may occur during the first few presentations of thestimulus.

14. Sensitization by stimuli from anothermodalityb (e.g., Swithers & Hall, 1994)

An increase in responsiveness to a stimulus may be produced by theintroduction of a stimulus from another modality (e.g., a light or noise).

a Characteristic of habituation has been confirmed for operant responding for food or water. b Characteristic has been confirmed for drugintake.

165HABITUATION AND DRUG CONSUMPTION

habituation proceeds long enough for the drug to lose itseffectiveness as a reinforcer. Consumption might resumebecause responsiveness to a habituated stimulus recoverswhen that stimulus is absent for a time (spontaneous recov-ery, Characteristic 1, Table 1).

Because our model describes drug consumption, it alsohas implications for understanding and controlling addic-tion. We predict that addiction is likely when a drug servesas a particularly strong reinforcer and when habituation isweak or sensitization is strong to that reinforcer. Equatingaddiction with strong reinforcement may seem circular, butour model is predictive because we have independent mea-sures for reinforcer strength and for the strength of sensiti-zation and habituation. The effectiveness of a reinforcer canbe measured in several ways. Shifts in either the dose-response curve, or the breakpoint of a progressive ratioschedule maintained by the drug, are familiar to researcherswho study drugs. A third measure, preference for a drug, istaken from the basic operant literature (e.g., Baum, 1974;Miller, 1976). According to preference measures, strongreinforcers are those that support higher response rateswhen the animal has a choice between that reinforcer and aqualitatively different reinforcer (e.g., food, water). Thestrength of sensitization and habituation to a drug can bemeasured by examining the within-session pattern of oper-ant responding for that drug. Drugs that are liable to abuseshould produce strong sensitization and weak habituation asobserved in the top graph of Figure 1. In addition, thefactors that alter the speed and strength of sensitization andhabituation are relatively well understood (see Table 1).Therefore, as will be discussed, we make many predictionsabout how drug consumption and addiction can be under-stood and controlled (see, e.g., the Implications for theControl of Human Drug Intake section). However, in spiteof our predictions about addiction, the regulation of drugconsumption remains the primary focus of our model.

In the current article, we review evidence that supportsthis sensitization–habituation model of drug consumption.To clarify our model, we briefly compare it with alternativepsychological models of drug consumption and addiction.Then we show that drug consumption shows many of theempirical characteristics of behavior undergoing sensitiza-tion–habituation. In particular, we argue that a depressiveprocess must be postulated to explain drug intake, and thatthis process exhibits many of the empirical characteristics ofhabituation. These characteristics include acute and chronictolerance, the effect of deprivation on consumption, thecontextual specificity of tolerance, polydrug abuse, and therelationship between stress and tolerance. Next we arguethat an activating process must also be postulated to explaindrug taking, and this activating process shares the empiricalcharacteristics of sensitization. The characteristics that arediscussed include behavioral sensitization, priming, rein-statement, and cross-sensitization between stress and drugtaking. Several of these characteristics are counterintuitiveand, therefore, provide relatively strong support for anymodel that can explain them.

Although sensitization usually precedes habituation, wediscuss the contribution of habituation before that of sensi-

tization because the characteristics of habituation are betterunderstood than those of sensitization (see Table 1). Inaddition, some aspects of drug consumption have beenattributed to habituation in the past (e.g., Baker & Tiffany,1985). Therefore, readers may be more familiar with theidea that habituation helps to regulate drug consumptionthan they are with the idea that sensitization contributes.Our review of the literature is necessarily incomplete. Weassume that the phenomena that we discuss are well known.Therefore, we cite only a few references to support each ofour conclusions.

Comparison With Similar Psychological Theories

We clarify our model by comparing it with similar psy-chological models of drug consumption or addiction. Be-cause of space limitations, we discuss only a few models.Our discussion is brief and, therefore, is limited. We do notdiscuss very dissimilar psychological models (e.g., Tiffany,1990). We also fail to evaluate physiological models. Ourmodel analyzes drug consumption at the behavioral level.We predict that whatever physiological mechanisms even-tually explain operant conditioning and sensitization–hab-ituation to the reinforcer also help to regulate drug con-sumption. Beyond that, our model does not make strongphysiological predictions.

Other Habituation Theories

We are not the first to suggest that habituation contributesto the regulation of drug taking (e.g., Kesner & Baker, 1981;Paletta & Wagner, 1986). We discuss Baker and Tiffany’s(1985) theory as an example of these prior models. Bakerand Tiffany postulated that habituation contributes to toler-ance for morphine. As habituation reduces an animal’ssensitivity to morphine, the animal requires more morphineto produce the drug state formerly produced by a smallamount of the drug. That is, tolerance occurs.

Our model differs from Baker and Tiffany’s (1985)model in several ways. First, their model applies to mor-phine. Our model applies to any drug that serves as areinforcer. Second, Baker and Tiffany emphasized the roleof habituation, but they referred to sensitization as “anom-alous.” Our model formally incorporates the role of sensi-tization. Third, Baker and Tiffany’s theory is based on thetheoretical explanation for habituation proposed by Wagner(1976). In contrast, we take an empirical approach. Webelieve that an empirical approach is necessary because themany theories of habituation that have been proposed (e.g.,Sokolov, 1963; Wagner, 1976) have all been criticized (e.g.,Mackintosh, 1987; Staddon & Higa, 1996). Fourth, Bakerand Tiffany focused on the role of habituation in the devel-opment of tolerance. We postulate instead that habituationplays a role in regulating drug consumption. Our modelsuggests an explanation for many additional phenomena inthe drug literature (e.g., priming, reinstatement, behavioralsensitization) because these phenomena are characteristicsof behavior undergoing sensitization and habituation. Fi-nally, the current model is tied to, and extends, research


about dynamic changes in the effectiveness of conventionalreinforcers (e.g., McSweeney, Hinson, & Cannon, 1996).Baker and Tiffany’s model is not tied to this literature.

Classical Conditioning

Many researchers have proposed classical conditioningmodels of drug consumption and addiction (e.g., Ludwig &Wikler, 1974; Wikler, 1948). We discuss Siegel’s (1975,1977) compensatory-response model as an example. Siegelargued that classical conditioning of compensatory condi-tioned responses (CRs) may help to explain tolerance andwithdrawal to drugs. In particular, he argued that drugsserve as unconditioned stimuli (USs) in classical condition-ing. As a result, a CR develops to any neutral stimulus thatpredicts the drug (conditioned stimulus [CS]). Siegel furtherargued that the CR is opposite in form to the responseevoked by the drug itself (the unconditioned response[UR]). Classically conditioned CRs build up gradually overtrials as a CS repeatedly predicts a US. Tolerance occurs todrugs because the strengthening CR increasingly opposesthe primary action of the drug US. As a result, more andmore of the drug is needed to evoke the same UR (the“high”). When a drug-associated CS occurs in the absenceof the drug, the CR occurs without the UR. Because that CRis opposite to the high evoked by the US, drug-associatedCSs evoke a “low” that might be called withdrawal whenthe CSs are presented without the drug.

Our model is similar to Siegel’s (1975) model in severalways. Both models are primarily empirical. That is, Siegeldoes not present a theory of classical conditioning. Instead,he argues that drug consumption shows many of the empir-ical properties of behavior undergoing classical condition-ing (e.g., specificity, Siegel, 1975; latent inhibition, Siegel,1977; extinction, Siegel & Sdao-Jarvie, 1986; external in-hibition, Siegel & Sdao-Jarvie, 1986; partial reinforcement,Siegel, 1977; blocking, Dafters, Hetherington, & McCart-ney, 1983; overshadowing, Walter & Riccio, 1983). We donot postulate a theory of habituation. Instead, we supportour model by showing that drug consumption exhibits theempirical properties of behavior undergoing habituation.

Situations that produce operant conditioning often pro-duce classical conditioning and vice versa (see, e.g., Rach-lin, 1973). Therefore, it would not be surprising if thepresentation of drugs supported both classical (Siegel’s[1975, 1977] model) and operant (our model) conditioning.In fact, the same theoretical mechanism may underlie thetwo types of conditioning. If this is true, then our model andthat of Siegel (1975) may be closely related.

For now, however, we can also identify some differencesbetween the models. To begin with, the models make some-what different predictions because the empirical propertiesof habituation (see Table 1) and classical conditioning (e.g.,latent inhibition, blocking; see list given above) are some-what different.

Siegel’s (1975) theory primarily addresses the develop-ment of tolerance and withdrawal. Our model addresses theregulation of drug consumption. Unlike Siegel, we have noobvious explanation for withdrawal. We cannot explain

why withdrawal is often opposite to the acute effects of thedrug (e.g., Kalant, LeBlanc, & Gibbins, 1971) or why theintensity of withdrawal is sometimes related to the devel-opment of tolerance (e.g., Hinson & Siegel, 1980; Poulos &Cappell, 1991).

Our explanation for tolerance also differs from that ofSiegel. Siegel (1975, 1977) proposes an interfering responseexplanation. That is, tolerance occurs when drug-associatedCSs evoke a response that is opposite in direction to, andthat therefore interferes with, the response evoked by thedrug itself. Our model predicts tolerance because habitua-tion reduces an animal’s sensitivity to the drug (see thefollowing sections: A Depressive Process Develops WithDrug Intake and Long-Term Habituation). As a result, Sie-gel’s (1975, 1977) model, but not the current one, predictsthat a compensatory CR develops to drug-associated stim-uli. This has been confirmed in some studies (e.g., Crowell,Hinson, & Siegel, 1981), but it has also been contradictedby many studies that report tolerance in the absence of sucha compensatory CR (e.g., Cepeda-Benito, Tiffany, & Cox,1999; see Baker & Tiffany, 1985, for a review) or that showthat stimuli that predict drugs are appetitive or positivelyreinforcing rather than aversive (e.g., Geier, Mucha, &Pauli, 2000). In fact, Ramsay and Woods (1997) argued thatthe CR always resembles, rather than opposes, the UR to thedrug when the CR is properly measured.

Incentive and Reinforcement Accounts

Psychomotor stimulation. Wise and Bozarth (1987) ar-gued that the ability of a drug to cause addiction is relatedto its ability to cause psychomotor activation. This occursbecause the forebrain dopamine system underlies both theability of the drug to serve as a psychomotor stimulant andas a reinforcer. Addiction occurs when the drug serves as apowerful reinforcer.

Our model is similar to Wise and Bozarth’s (1987)model. As indicated, both models attribute drug consump-tion and addiction to the ability of drugs to serve as positivereinforcers. Both models tie addiction to psychomotor stim-ulation, although in slightly different ways. We argue thatsensitization, as it is studied in the literature on sensitiza-tion–habituation, contributes to the behavioral sensitizationthat is often observed to drugs (see the An ActivatingProcess May Develop With Drug Intake section). Behav-ioral sensitization is usually measured by an increase in thedrug’s ability to serve as a reinforcer or by an increase in thedrug’s ability to elicit motor activation. Wise and Bozarth’stheory focuses on the motor activation aspect of behavioralsensitization. They argued that an increase in psychomotorstimulation is tied to the abuse potential of the drug. Ourmodel focuses on the reinforcer effectiveness aspect. Weargue that drugs are particularly liable to abuse when theyserve as strong reinforcers. Nevertheless, because the in-crease in reinforcer effectiveness and the increase in psy-chomotor stimulation occur together so often that they aredescribed by the same name (behavioral sensitization), webelieve that the two models are making a similar point.

The models also differ in some ways. To begin with,


Wise and Bozarth’s (1987) theory is primarily a theory ofaddiction. As indicated, our model primarily describes drugconsumption. Wise and Bozarth also present a physiologicalmechanism for addiction (forebrain dopamine system), butthey have little to say about a behavioral mechanism. Ourmodel presents a behavioral mechanism (sensitization–ha-bituation to the drug reinforcer), but it has little to say abouta physiological mechanism. The need for a physiologicalmechanism is probably obvious, but we believe that pro-viding a behavioral mechanism is equally important. Forexample, as described later, behavioral models provide sug-gestions about how to alter drug consumption by manipu-lating the environment (e.g., Table 1) without directly ma-nipulating the animal’s physiology.

Positive incentive account. Stewart, de Wit, and Eikel-boom (1984) argued that opiate and stimulant drugs act oncommon physiological substrates (e.g., mesolimbic dopa-mine path) to generate positive appetitive states that main-tain drug taking. Stimuli that are associated with drugsmimic the states produced by drugs, not the opposite states(e.g., Siegel, 1975). As a result, drug-associated stimulitrigger relapse by increasing the probability of drug-relatedthoughts and actions.

Stewart et al.’s (1984) theory has much in common withour model. As our model, it primarily describes drug taking.Similar to our emphasis on positive reinforcement, Stewartet al. emphasize the role of positive, rather than negative,states in maintaining drug consumption. They also associatethe positive incentive states generated by drugs with thestates generated by other incentive stimuli, such as food andwater. Similarly, we argue that drugs serve as reinforcers inthe same manner as more commonly studied reinforcerssuch as food and water.

However, Stewart et al.’s (1984) theory also differs fromours in several ways. As a minor point, they restrict theirtheory to opiates and stimulant drugs. Our model applies toany drug that acts as a reinforcer. They also attribute drugtaking to incentive motivational states rather than to rein-forcement. Incentive motivational states alter the salienceand effectiveness of conditioned and unconditioned incen-tive stimuli (e.g., USs in classical conditioning). We at-tribute drug taking to positive reinforcement (i.e., to theability of drugs to increase the frequency of behaviors thatthey follow). The two terminologies may be only two dif-ferent ways of talking about the same phenomenon. Never-theless, we favor reinforcement terminology because it pro-vides a simple empirical test for the presence and strength ofreinforcement. In contrast, incentive motivational statesseem harder to identify and to measure.

Incentive sensitization theory. Robinson and Berridge(1993, 2001) argued that drugs serve as rewards. Addictionoccurs when the neural system that attributes incentivesalience to a stimulus (e.g., a drug) becomes sensitized. Thiscauses compulsive motivation for, or wanting of, the drugthat can occur even if the addict does not report liking thedrug.

Robinson and Berridge’s (2001) theory is phrased interms that differ from ours. Robinson and Berridge talk ofrewards that have several different functions: They support

learning; they induce affect or emotion (liking); and theymotivate actions aimed at obtaining the drugs (wanting;Berridge & Robinson, 2003). Robinson and Berridge at-tribute addiction to a change in wanting of the drug. Ourmodel attributes drug taking to reinforcement. However,this distinction may be more apparent than real. It seemsreasonable to identify the wanting aspect of reward withreinforcement. The terms both address the drug’s ability tomotivate (wanting) and support (reinforcement) behaviordirected toward the drug. In that case, the two theoriesattribute drug consumption to fundamentally similar mech-anisms (wanting and reinforcement).

Robinson and Berridge’s (2001) theory is primarily atheory of addiction. As indicated, our model primarily ad-dresses drug consumption. Although both models argue thatsensitization plays a role in addiction, the models use theterm “sensitization” in different ways. Robinson and Ber-ridge’s sensitization leads to psychomotor stimulation. As aresult, they predict that drugs that induce psychomotorstimulation should be liable to abuse. Our sensitization isstudied in the literature on sensitization–habituation. As aresult, we predict that drug consumption and addiction willshow the empirical properties of behavior undergoing sen-sitization and habituation (see Table 1). As described later,our theory makes many predictions that are not made byRobinson and Berridge’s theory.

Negative reinforcement. Many theories attribute drugtaking to escape from, or reduction of, an aversive stimulus(i.e., to negative reinforcement). For example, Baker, Piper,McCarthy, Majeskie, and Fiore (2004) argued that addictslearn to detect interoceptive cues of negative affect precon-sciously over cycles of drug use and withdrawal. Whenstressors or abstinence cause negative affect to becomeconscious, the affect promotes renewed drug administrationby increasing “hot” information processing and decreasing“cool” information processing. Hot information processingbiases attentional and response selection processes towardresponses that have most efficiently ameliorated negativeaffect in the past (i.e., toward drug taking). Cool informa-tion processing biases responding toward coping andregulation.

Baker et al.’s (2004) model is similar to ours in that bothmodels attribute drug consumption and addiction to rein-forcement. Both models also argue that stress plays a role indrug taking. However, the models also differ in many ways.To begin with, the models attribute the effect of stress todifferent processes. According to Baker et al., stress causesrelapse because it increases negative affect and thereforeshifts cognitive resources to hot information processing. Inaddition, addicts learn to consume drugs during times ofstress because drug taking is negatively reinforced by stressreduction. In contrast, we argue that stress increases drugtaking because stressors act as sensitizers (Characteristic 14,Table 1). As a result, they increase responsiveness to drugsand, therefore, increase the ability of drugs to serve aspositive reinforcers.

Baker et al.’s (2004) model focuses on addiction. Ourmodel focuses primarily on drug consumption. Accordingto Baker et al., addicts avoid the negative affect that accom-


panies drug withdrawal. Affect, defined as a conscious feel-ing of liking or disliking, plays no role in our model.Similarly, our model does not address the topic of drugcravings. Our model argues that drug consumption is me-diated by the ability of drugs to serve as reinforcers (i.e.,their ability to increase the frequency of responses that theyfollow). We take no position on whether the processes thatsubserve addiction are conscious. We also do not knowwhether reinforcers are liked. As argued, we believe thatreinforcement is related to the wanting, but not necessarilyto the liking, of drugs (e.g., Nesse & Berridge, 1997).

Baker et al. (2004) argued that increasing negative affectincreases hot information processing and decreases coolinformation processing. We take no position on the role ofcognitive processing in drug consumption and addiction. Asa result, the two theories make different predictions. Forexample, Baker et al. predict that negative affect is associ-ated with withdrawal from all types of drugs. We do notmake this prediction. Instead, as will become clear, wemake predictions about many variables that play no role inBaker et al.’s model (e.g., priming, reinstatement).

Some have argued that contemporary theories of addic-tion can be categorized according to whether drug taking ismotivated positively by the appetitive pursuit of drugs ornegatively by escape from the aversive aspects of drugwithdrawal (e.g., Tiffany, 1990). Our model attributes drugconsumption to positive reinforcement. Baker et al. (2004)attribute addiction to negative reinforcement. Our modelcould be adapted to apply to negative reinforcement. Ha-bituation alters the ability of aversive stimuli to serve asnegative reinforcers (e.g., Jerome, Moody, Connor, & Ryan,1958) and punishers (e.g., Azrin, 1960), just as it alters theeffectiveness of positive reinforcers. As a result, a versionof our model could be formulated in which drug consump-tion is negatively reinforced (e.g., by escape from with-drawal symptoms) and sensitization–habituation modulatesthe ability of these negative reinforcers to support drugconsumption. We formulated our model in terms of positivereinforcement because most of the experiments on habitu-ation to the reinforcer were conducted with positive rein-forcers. In principle, however, our model could be extendedto negative reinforcement.

Conclusion

The following characteristics distinguish our model fromother similar psychological models. Our model is primarilya model of drug consumption, rather than a model of ad-diction or of tolerance and withdrawal. Our model attributesdrug consumption to reinforcement rather than to cognitiveor affective processes. We emphasize the role of operantconditioning, as modulated by sensitization–habituation,rather than the role of classical conditioning. Our view ofreinforcement derives from Skinner’s (1938) empirical, be-havior-analytic approach, rather than from incentive moti-vational theory. We emphasize the role of positive, ratherthan negative, reinforcement in maintaining drug taking;however, in principle, our model could be extended to applyto negative reinforcement. Our model is empirical. We do

not have a theory of either operant conditioning or sensiti-zation–habituation. Instead, we look for empirical common-alities between the characteristics of drug taking and thecharacteristics of habituation and conditioning. Neverthe-less, we must acknowledge that our model provides anincomplete explanation for drug taking (see the ProblemsWith the Current Model section). As a result, it seems likelythat the processes postulated by our model will need to besupplemented by the processes postulated by other models(e.g., classical conditioning) to provide a complete model.

A Depressive Process Develops With Drug Intake

Many authors have argued that a process that limits drugintake must be postulated to explain drug seeking and drugtaking (e.g., Olmstead, Parkinson, Miles, Everitt, & Dick-inson, 2000). The development of acute tolerance providesevidence for such a process. Acute tolerance occurs whendrug concentration is held constant, but response to the drugdecreases toward control levels over time (Ramsay &Woods, 1997). Acute tolerance is usually measured duringinitial administration of the drug to separate it from chronictolerance (see the Long-Term Habituation section).

Acute tolerance probably arises from the influence ofseveral different processes (e.g., Cepeda-Benito et al., 1999;Fadda & Rossetti, 1998; Mucha, Geier, & Pauli, 1999).Baker and Tiffany (1985) argued that habituation is one ofthose processes. For example, they showed that deliveringlarge doses of the drug (Characteristic 8, Table 1) anddelivering them at short interdose intervals (Characteris-tic 6, Table 1) promote the development of tolerance (Baker& Tiffany, 1985), as they should if habituation contributesto tolerance.

At first glance, the large variability in tolerance may seemincompatible with habituation. Tolerance may develop forsome, but not other, effects of the drug. For example,tolerance may develop to the aversive or depressant, but notto the positive or activating, aspects of drugs (Masur &Boerngen, 1980; Stewart et al., 1984). The same drug canproduce tolerance in one measure and behavioral sensitiza-tion in another. For example, the repeated administration ofmorphine may produce tolerance to its analgesic effects(Kornetsky & Bain, 1968) and behavioral sensitization to itslocomotor-stimulating effects (Babbini, Gaiardi, & Barto-letti, 1975; Kalivas & Stewart, 1991). Tolerance may alsoappear in one situation, whereas behavioral sensitizationmay appear in another. For example, rats given a continuousinfusion of (�)-4-propyl-9-hydroxynapthoxazine (PHNO)over several days show tolerance to the locomotor effects ofPHNO during the light period of a 12-hr light/dark cycle butbehavioral sensitization during the dark (Martin-Iverson,Iversen, & Stahl, 1988; Martin-Iverson, Stahl, & Iversen,1988; Ruzich & Martin-Iverson, 2000). If the light/darkcycle is reversed, then tolerance and behavioral sensitiza-tion also reverse in a few days.

This variability has led some authors to reject the ideathat habituation contributes to tolerance. For example,Fadda and Rossetti (1998) asserted, “. . .that habituationdevelops to all effects of the drug and at the same rate” (p.


389). We argue instead that sensitization and habituation arealso highly variable. Habituation occurs at different rates todifferent stimuli (e.g., Hinde, 1970). When more than onemeasure of responsiveness to a stimulus is recorded, themeasures may differ in the rate and degree of habituation(e.g., Peeke & Peeke, 1973; Shalter, 1984). In addition,sensitization does not occur for all stimuli (e.g., Groves &Thompson, 1970). For example, salivation to olfactory cuesshows sensitization (Wisniewski, Epstein, & Caggiula,1992), but salivation to gustatory cues usually does not(Epstein, Caggiula, Perkins, Mitchell, & Rodefer, 1992;Epstein, Rodefer, Wisniewski, & Caggiula, 1992). In ouropinion, variability in the development of tolerance to drugssupports, rather than challenges, the habituation hypothesis.

The Depressive Process Resembles Habituation

Spontaneous Recovery (Characteristic 1, Table 1)

The depressive process in drug taking shares many of theempirical characteristics of habituation listed in Table 1.Spontaneous recovery refers to an increase in responsive-ness to a habituated stimulus after a period without contactwith that stimulus (Thompson & Spencer, 1966). The sizeof spontaneous recovery usually increases with time sincelast contact, at least up to a point (e.g., Leibrecht & Askew,1969).

Deprivation is not necessary for drugs to act as reinforc-ers, just as deprivation is not necessary for highly attractivefoods to act as reinforcers (e.g., M. J. Morgan, 1974).Nevertheless, consistent with spontaneous recovery, depri-vation for a drug may increase the reinforcing efficacy ofthat drug. For example, deprivation of nicotine in smokersincreases operant responding for cigarette reinforcers (Say-ette, Martin, Wertz, Shiffman, & Perrot, 2001). Deprivationof cocaine increases the ability of cocaine to serve as areinforcer in rats (D. Morgan, Brebner, Lynch, & Roberts,2002).

The alcohol deprivation effect (ADE) refers to an in-crease in the intake of, and preference for, ethanol withethanol deprivation (e.g., Heyser, Schulteis, & Koob, 1997;Li et al., 2001; McKinzie et al., 1998; Sinclair & Li, 1989;Sinclair & Senter, 1968). It is a robust effect that is found inboth rats (McKinzie et al., 1998) and humans (Mello &Mendelson, 1972). Although some have argued that theADE results from a change in consummatory responding,rather than from a change in reinforcer efficacy (Samson &Chappell, 2001), others have shown that deprivation doesincrease the effectiveness of ethanol as a reinforcer. Forexample, consistent with the current hypothesis, the breakpoint on a progressive ratio schedule is higher after alcoholdeprivation than during initial baseline drinking (Spanagel& Holter, 1999, 2000).

Stimulus Specificity (Characteristic 2, Table 1)

Habituation is relatively specific to the precise nature ofthe stimulus that is delivered. As a result, changes in thatstimulus disrupt habituation and restore responsiveness to

the stimulus (Peeke, 1984; Peeke & Veno, 1973; Swithers &Hall, 1994; Whitlow, 1975). Many studies have reportedthat changing the experimental context disrupts tolerance toa drug (e.g., Adams, Yeh, Woods, & Mitchell, 1969; Ce-peda-Benito et al., 1999; Cepeda-Benito & Tiffany, 1996;Siegel, 1975, 1977; but see also Pinel & Puttaswamaiah,1985). These studies may provide evidence for stimulusspecificity if it is assumed that the context is part of thestimulus to which the participant habituates. In that case, achange of context disrupts tolerance by violating the stim-ulus specificity of the habituation that contributes to thattolerance.

Variety Effects (Characteristic 3, Table 1)

Perhaps because of stimulus specificity, habituation isslower if a variety of stimuli are presented than if only oneis available. If drug stimuli show variety effects, then accessto a variety of drugs should serve as a more powerfulreinforcer than any one drug alone. Consistent with ourargument, abusing a variety of drugs is more common thanabusing a single drug (polydrug abuse, Chan, 1991). Inaddition, a combination of drugs is often preferred to eitherdrug alone (e.g., Meisch & Lemaire, 1990). For example,cocaine–heroin (Duvauchelle, Sapoznik, & Kornetsky,1998; Mello et al., 1995; Ranaldi & Munn, 1998), metha-done–ethanol (Shelton, Macenski, & Meisch, 1998), andcocaine–ethanol (Wang, Brown, Grabowski, & Meisch,2001) combinations are more reinforcing than the samedose of either component drug presented alone.

Dishabituation (Characteristic 4, Table 1)

Dishabituation is the restoration of responsiveness to ahabituated stimulus by the presentation of a strong, differ-ent, or extra stimulus (Thompson & Spencer, 1966). Con-sistent with our argument, the introduction of extraneousstimuli may disrupt tolerance (Poulos, Hunt, & Cappell,1988; Siegel & Larson, 1996; Siegel & Sdao-Jarvie, 1986)and increase the reinforcing efficacy of drugs. For example,tail pinches (e.g., Piazza, Deminiere, Le Moal, & Simon,1990) and noncontingent foot shocks (Goeders & Guerin,1994) increase the efficacy of stimulant reinforcers in rats(see Sinha, 2001, for a review of the effect of stressors ondrug consumption).

Researchers disagree about whether introducing extrane-ous stimuli restores responsiveness to a habituated stimulusby increasing sensitization (e.g., Groves & Thompson,1970) or by disrupting habituation (e.g., Marcus, Nolen,Rankin, & Carew, 1988), as the name “dishabituation”implies. As a result, findings in the habituation literature areoften arbitrarily described as dishabituation if the addedstimulus restores responsiveness to an already habituatedstimulus and as sensitization if the added stimulus increasesresponding before substantial habituation occurs (e.g., Mar-cus et al., 1988). Therefore, the studies cited in later sections(Sensitization by Extraneous Stimuli—Drugs and Stress,Sensitization by Extraneous Stimuli—Reinstatement) mightalso be considered to be evidence for dishabituation.


Stimulus Rate (Characteristic 6, Table 1)

Habituation is usually faster and more pronounced whenstimuli are presented at faster than at slower rates (Thomp-son & Spencer, 1966). As indicated earlier, Baker andTiffany (1985) showed that tolerance for morphine isgreater and develops more quickly when interdose intervalsare small than when they are large (e.g., Seaman, 1985).This finding was reported when the doses were unsignaledbut possibly not when they were signaled (Kayan, Woods,& Mitchell, 1969; Mushlin, Grell, & Cochin, 1976).

If confirmed, then the failure to find the predicted effectof rate of stimulus presentation for signaled drugs mightcontradict the current argument. Alternatively, it may indi-cate that signaling a drug introduces additional processessuch as classical conditioning. These additional processesmight obscure the predictions of the current model. Forexample, Siegel (1975) argued that stimuli that predict thepresentation of a drug evoke a response that is opposite indirection to the response evoked by the drug itself (see theClassical Conditioning section). The predictions of a modelthat postulated the occurrence of habituation to the CS (thedrug-associated stimuli), habituation to the US (the drug),and the occurrence of compensatory CRs would be muchmore complicated than the predictions of our simple habit-uation model.

Stimulus Exposure (Characteristic 8, Table 1)

Responsiveness to a repeatedly presented stimulus de-creases with increases in stimulus exposure (e.g., Thompson& Spencer, 1966). Consistent with this characteristic, Bakerand Tiffany (1985) argued that tolerance is greater anddevelops more quickly at higher than at lower doses ofmorphine. It seems reasonable to assume that higher dosesof a drug provide more exposure to the drug than lowerdoses. Cocaine administration decreases the response ratemaintained by cocaine or another reinforcer (Gerber,Bozarth, Spindler, & Wise, 1985). Pretreatment with free-base nicotine also reduces the rate of self-administration ofintravenous nicotine (Green, Phillips, Crooks, Dwoskin, &Bardo, 2000).

Long-Term Habituation (Characteristic 9, Table 1)

Many authors distinguish between short-term habituationthat develops within sessions and long-term habituation thatis learned and persists over time (e.g., Wagner, 1976). Ifhabituation contributes to tolerance, then both a short-termand a long-term form of tolerance should be observed.Consistent with our argument, many authors have distin-guished between acute and chronic tolerance (Kalant et al.,1971). Chronic tolerance is postulated because many studiesshow that tolerance may be retained over weeks of nonex-posure to the drug (e.g., Mushlin et al., 1976; Siegel, 1975)and may be learned (e.g., Chen, 1979; Schuster, Dockens, &Woods, 1966; Siegel, 1976, 1978; Wenger, Tiffany, Bom-bardier, Nicholls, & Woods, 1981).

Generality (Characteristic 12, Table 1)

Habituation occurs for most, if not all, stimuli and formost, if not all, animals (e.g., Thorpe, 1966). For example,Harris (1943) reported habituation in unicellular organismssuch as amoeba. Likewise, the characteristics of drug takingreported here occur for many species of animals takingmany different types of drugs.

An Activating Process May Develop WithDrug Intake

Drugs May Activate Behavior

Habituation is often accompanied by sensitization (e.g.,Groves & Thompson, 1970; see Figure 1). Therefore, if thecurrent model is correct, then an activating process similarto sensitization should be observed in drug taking. Consis-tent with this argument, several authors have argued that anactivating process must be postulated to explain drug intake(e.g., Olmstead et al., 2000). Similar to sensitization (e.g.,Epstein, Caggiula, et al., 1992; Epstein, Rodefer, et al.,1992), this stimulant process may not develop for all classesof drugs (e.g., cannabinoids). Nevertheless, even drugs thatare known primarily for their depressant effects (e.g., alco-hol, barbiturates, opiates) have behavioral-activating effects(Di Chiara, Acquas, & Carboni, 1992; Domino, Vasko, &Wilson, 1976). For example, low doses of ethanol stimulate,rather than depress, locomotor activity, particularly in ani-mals that are bred to prefer ethanol (Grahame, Rodd-Hen-ricks, Li, & Lumeng, 2000; Rodd-Henricks, McKinzie,Crile, Murphy, & McBride, 2000).

According to our argument, sensitization, the process thatproduces this behavioral activation (e.g., an increase inlocomotion), also increases the effectiveness of the drug asa reinforcer. Highly reinforcing drugs should be more liableto addiction than less reinforcing drugs because highlyreinforcing drugs strengthen their own intake to a greaterextent than less reinforcing drugs. As a result, our modelpredicts that the degree to which drugs activate behaviorshould be related to their tendency for abuse. (Also see thePsychomotor stimulation section.)

Some evidence taken from self-report measures is con-sistent with this idea. When the activating and sedatingproperties of alcohol are separated, vulnerability to heavydrinking (Gabrielli, Nagoshi, Rhea, & Wilson, 1991; Hold-stock, King, & de Wit, 2000) and greater intake of alcohol(de Wit, Pierri, & Johanson, 1989) are associated withenhanced sensitivity to the activating, and reduced sensitiv-ity to the sedating, effects of alcohol. Those who preferalcohol to a placebo also report more alcohol-induced ela-tion and vigor and less fatigue and confusion in response toalcohol than those who choose the placebo (de Wit, Uhlen-huth, Pierri, & Johanson, 1987).

More direct behavioral measures provide additional evi-dence for the predicted relation between the activating ef-fect of a drug and its potential for abuse. The size of theincrease in resting heart rate that occurs in response toalcohol is directly proportional to the reinforcing efficacy ofalcohol (Fowles, 1983). Individuals who consume more


alcohol in the laboratory show greater alcohol-induced in-creases in heart rate than those who consume less alcohol(Conrod, Peterson, & Pihl, 1997). Those with a familyhistory of alcoholism also show increased sensitivity to theactivating effects of alcohol measured by increases in heartrate (Conrod, Pihl, & Ditto, 1995; Conrod, Pihl, & Vassil-eva, 1998; Finn & Pihl, 1988; Finn, Zeitouni, & Pihl, 1990;Newlin & Thomson, 1991, 1999; Peterson et al., 1996). Infact Conrod, Peterson, and Pihl (2001; see also Wise &Bozarth, 1987) argued that the addictive liability of a drugdepends on its ability to produce “psychomotor stimulation”but not necessarily “euphoria.” Admittedly, these findingsmay be of limited generality. To date, most results havebeen demonstrated only for alcohol. Nevertheless, if thecurrent model is correct, then similar relationships should befound for other drugs.

Behavioral Sensitization

Different authors have defined behavioral sensitization indifferent ways (cf. Kalivas & Stewart, 1991; Vanderschuren& Kalivas, 2000). For our purposes, behavioral sensitiza-tion is an increase in the effectiveness of a drug afterrepeated administrations of that drug or other similar drugs(for reviews, see Kalivas, Duffy, Abhold, & Dilts, 1988;Post, Weiss, & Pert, 1987; Robinson & Becker, 1986). Weargue that sensitization, as it is studied in the literature onsensitization–habituation (an increase in responsiveness to astimulus with its initial presentations), contributes to thebehavioral sensitization observed in the drug literature (anincrease in the effectiveness of a drug after repeated pre-sentations). Although our argument may sound circular, itactually ties together two different literatures. It predictsthat the characteristics of sensitization reported in the ha-bituation literature will also be characteristics of behavioralsensitization in the drug literature.

Consistent with our prediction that sensitization shouldincrease the effectiveness of drugs as reinforcers, an in-crease in the effectiveness of the drug as a reinforcer isfrequently used as an index of behavioral sensitization (e.g.,Horger, Shelton, & Schenk, 1990; Mendrek, Blaha, & Phil-lips, 1998; Numan, 1981; Piazza, Deminiere, Le Moal, &Simon, 1989; Robinson & Berridge, 1993; Schenk & Da-vidson, 1998; Vanderschuren & Kalivas, 2000; Woolverton,Cervo, & Johanson, 1984). In fact, some authors haveincluded an increase in the positive reinforcing effects of thedrug in their definition of behavioral sensitization (e.g.,Vanderschuren, Schoffelmeer, Mulder, & De Vries, 1999a,1999b).

Behavioral sensitization is usually studied with stimu-lants (e.g., Post & Rose, 1976; Segal & Kuczenski, 1992).However, consistent with our argument, it has also beenreported for a variety of other drugs, including opiates(Battisti, Uretsky, & Wallace, 1999) and ethanol (e.g., New-lin & Thomson, 1991).

Sensitization shows a great deal of variability in theliterature on sensitization–habituation (e.g., Groves &Thompson, 1970). Consistent with our argument, suscepti-bility to behavioral sensitization for drugs varies greatly

across individuals (e.g., Robinson, 1988; Segal & Kuczen-ski, 1987) and across strains of mice and rats (e.g., Cun-ningham, Niehus, Malott, & Prather, 1992; Glick, Shapiro,Drew, Hinds, & Carlson, 1986; Shuster, Webster, & Yu,1975; Shuster, Yu, & Bates, 1977). In addition, the timecourse of behavioral sensitization differs for different drugs(e.g., Kalivas & Stewart, 1991).

Sensitization comes in both short- and long-term forms inthe literature on sensitization–habituation. For example, asingle shock to an animal’s tail will produce short-termsensitization that lasts minutes. Five or more shocks willproduce a long-term form of sensitization that lasts for daysor weeks (Kandel, Schwartz, & Jessel, 2000, p. 1250; seealso Carew, 1984; Pinsker, Hening, Carew, & Kandel,1973). Consistent with our argument, short- and long-termforms of behavioral sensitization have also been identified.The short-term form (acute sensitization) is an increase inthe effect of a drug despite constant levels of the drug(Martin & Moss, 1993; Newlin & Thomson, 1990, 1991).The long-term form (chronic sensitization) refers to sensi-tization that is both long lasting and learned (Hinson &Poulos, 1981; Pert, Post, & Weiss, 1990; Post et al., 1987).

The Activating Process Resembles Sensitization

Sensitization by Initial Stimulus Presentations(Characteristic 13, Table 1)—Priming

Sensitization by initial stimulus presentations may con-tribute to priming. By initial stimulus presentations, wemean the first few times that a drug is presented to a naı̈veanimal and the first few times the drug is presented withina bout of consumption for an experienced animal. Forexample, the sensitization that appears in the top graph ofFigure 1 represents an increase in responding for a rein-forcer (sensitization) that occurs at the beginning of eachdaily session even after the animal has been exposed to thesame conditions of reinforcement for 25 sessions. It is worthrepeating that sensitization comes in both short- and long-term forms in the literature on sensitization–habituation(Kandel et al., 2000, p. 1250; see also Carew, 1984; Pinskeret al., 1973). The sensitization reported in Figure 1 isshort-term sensitization. It develops when stimulus expo-sure begins, but then it disappears between successive ses-sions of exposure. In long-term sensitization, sensitizationpersists even when long periods separate sessions of stim-ulus exposures (e.g., weeks).

We define priming as an increase in the desire, or rate ofoperant responding, for a drug that is produced by a predoseof that drug or a related drug. Other authors also haveincluded reinstatement under this heading (e.g., de Wit,1996). Reinstatement refers to the restoration of extin-guished conditioned responding by the presentation of partof the conditioning episode (e.g., Rescorla & Heth, 1975).We do not include reinstatement in our definition of primingbecause reinstatement involves a different procedure. Forexample, the stimulus delivered in a priming experiment isusually the drug itself or a related drug. The stimulusdelivered in a reinstatement procedure may be any part of


the conditioning episode (e.g., the CS, experimental con-text). Responding is conditioned and then extinguished instudies of reinstatement. Responding may be conditionedbut not extinguished in priming procedures. As a result ofthese procedural differences, reinstatement could be pro-duced by factors other than those that produce priming. Weargue below that sensitization also contributes to reinstate-ment (see the Sensitization by Extraneous Stimuli—Rein-statement section), but this is an empirical question thatshould not be confused by labeling the effects of twodifferent procedures with the same term.

Priming has been observed for many drugs, includingalcohol, amphetamine, nicotine, cocaine, and heroin (see deWit, 1996, for a review). Consistent with our argument,priming may be observed when the priming doses are giveneither immediately before (short-term sensitization), or longbefore (long-term sensitization), the test for the effect of thepredose. Also consistent with our argument, brief exposureto a drug increases the ability of that drug to act as areinforcer, as measured by an increased preference for thedrug or an increase in the rate of, or time spent making, anoperant response for the drug (Bigelow, Griffiths, & Lieb-son, 1977; Chutuape, Mitchell, & de Wit, 1994; de Wit &Chutuape, 1993; Ludwig, Wikler, & Stark, 1974). Preexpo-sure to amphetamine or nicotine also facilitates the acqui-sition of cocaine administration (Horger, Giles, & Schenk,1992).

Sensitization by Extraneous Stimuli(Characteristic 14, Table 1)—Drugs and Stress

Sensitization, as it is studied in the literature on sensiti-zation–habituation, may be produced by the introduction ofa stimulus from another modality (e.g., a noise; Swithers &Hall, 1994). Consistent with our model, Table 2 shows thatthe presentation of extraneous stimuli also increases theeffectiveness of drugs as reinforcers. Because the stimulithat produce these effects are often referred to as stressful(e.g., Lu, Shepard, Hall, & Shaham, 2003; Piazza & LeMoal, 1998), this finding is called cross-sensitization be-tween stress and drugs. The effect of stress on drug takingis complex, and the mechanisms by which these stimuliexert their effects are unclear (e.g., Lu et al., 2003). Nev-ertheless, the extraneous stimuli that sometimes increase theeffectiveness of drugs are exactly the sort of strong, salientstimuli that serve as sensitizers in the literature on sensiti-zation and habituation (e.g., electric shock; Kandel et al.,2000).

As argued, sensitization comes in both short-term andlong-term (learned) forms in the literature on sensitization–habituation. Consistent with our argument, Piazza and LeMoal (1998) argued the effect of extraneous stimuli on theefficacy of drug reinforcers may be either short or longlasting. Acute stressors facilitate drug taking only if theyclosely precede exposure to the drug. After prolonged ex-posure, facilitation of drug taking is found even if thestimulus is terminated weeks before the start ofself-administration.

Our argument attributes both behavioral sensitization andthe cross-sensitization of stress and drugs to the same pro-cess: sensitization. Consistent with this argument, the samestimuli produce both effects. For example, stress increasesdrug taking (Stewart & de Wit, 1987; Stewart et al., 1984).It also increases the motor stimulating actions of amphet-amine, cocaine, or morphine (e.g., Caggiula, Antelman,Aul, Knopf, & Edwards, 1989; Deroche et al., 1992; Kalivas& Duffy, 1989; Leyton & Stewart, 1990; Piazza et al.,1990). Food deprivation increases drug taking (see Table 2)and also increases the locomotor stimulating effects ofopiates, psychostimulants, and N-methyl-D-aspartate antag-onists (e.g., Bell, Stewart, Thompson, & Meisch, 1997;Cabeza de Vaca & Carr, 1998; Carr, Kim, & Cabeza deVaca, 2000, 2001; Piazza & Le Moal, 1996).

Sensitization by Extraneous Stimuli(Characteristic 14, Table 1)—Reinstatement

Reinstatement may provide further evidence for sensiti-zation by stimuli from another modality. Reinstatementrefers to the recovery of extinguished responding after thepresentation of part of the conditioning episode (the rein-

Table 2Studies Demonstrating That Extraneous Stimuli MayIncrease Drug Self-Administration, Drug Acquisition, orDrug Preference

Stimulus Sample confirming studies

Conditioned fearAlcohol Matsuzawa et al. (1998)

Electric shock or shock toanother animal

Cocaine Goeders & Guerin (1994)Ramsey & Van Ree (1993)

Opiates Shaham & Stewart (1994, 1995)Food deprivation

Amphetamine Campbell & Fibiger (1971)Deroche et al. (1993)

Cocaine Bell et al. (1997)Carr et al. (2000, 2001)Carroll & Meisch (1984)Comer et al. (1995)Specker et al. (1994)

Morphine Deroche et al. (1993)NMDA Cabeza de Vaca & Carr (1998)

Intraperitoneal injectionsof saline

Alcohol Little et al. (1999)Prenatal stress

Amphetamine Deminiere et al. (1992)Restraint

Opiates Shaham (1993, 1996)Social isolation

Amphetamine Jones et al. (1990)Cocaine Schenk et al. (1987)Morphine Hadaway et al. (1979)

Social stressCocaine Haney et al. (1995)

Miczek & Mutschler (1996)Tail pinch

Amphetamines Piazza et al. (1990)

Note. NMDA � N-methyl-D-aspartate.


stating stimulus; e.g., Pavlov, 1927; Rescorla & Heth,1975). Reinstatement has been shown in the operant re-sponding for many drugs. For example, presentation of thedrug reinstates extinguished responding that was previouslymaintained by nicotine, cocaine, amphetamine, or heroin(e.g., Chiamulera, Borgo, Falchetto, Valerio, & Tessari,1996; de Wit & Stewart, 1981, 1983; Stewart & Wise, 1992;Stretch & Gerber, 1973).

Reinstatement is often attributed to the retrieval of thememory of conditioning as a result of the delivery of a cuefor that conditioning (the reinstating stimulus; e.g., Bouton,1993) rather than to sensitization. However, at least oneprediction distinguishes sensitization from memory re-trieval. Sensitization predicts that reinstatement will occurwith the introduction of any strong stimulus, not just withthe introduction of stimuli that were involved in condition-ing. According to some versions of retrieval theory, a stim-ulus must be present during conditioning to restore thememory of conditioning (e.g., Delameter & LoLordo,1991). Unless generalization occurs, uninvolved stimulishould not retrieve the memory of conditioning becausethose stimuli were never associated with conditioning.

Much evidence has suggested that stimuli that were notpresent during conditioning can serve as reinstaters. Forexample, extinguished responding for cocaine or heroin isreinstated by the presentation of several other drugs (e.g.,De Vries, Schoffelmeer, Binnekade, & Vanderschuren,1999; de Wit & Stewart, 1981; Rush, Sullivan, & Griffiths,1995; Schenk & Partridge, 1999; Schenk, Partridge, &Shippenberg, 2000; Schenk, Worley, McNamara, & Vala-dez, 1996; Slikker, Brocco, & Killam, 1984). These resultsmight be attributed to generalization through common sub-jective or physiological effects (e.g., Schenk & Partridge,1999), but other examples are harder to explain in this way(e.g., Lu et al., 2003). For example, food deprivation rein-states extinguished responding for cocaine or heroin in ratsthat were not deprived during training (Carroll, 1985; Sha-lev, Highfield, Yap, & Shaham, 2000; Shalev, Marinelli,Baumann, Piazza, & Shaham, 2003). Foot shock reinstatesextinguished lever pressing that was formerly maintained byalcohol (e.g., Le et al., 1998), cocaine (e.g., Erb, Shaham, &Stewart, 1996), heroin (e.g., Shaham & Stewart, 1995), andnicotine (e.g., Buczek, Le, Wang, Stewart, & Shaham,1999).

Although Ahmed and Koob (1997) argued that even theseresults might be attributed to generalization, Buczek et al.(1999) criticized their argument. For example, they arguedthat the effect of stress as a reinstater is equal to or greaterthan the effect of the drug itself as a reinstater (Erb et al.,1996; Le et al., 1998; Lu et al., 2003; Shaham, 1996;Shaham, Adamson, Grocki, & Corrigall, 1997). If stressexerted its effect because of generalization, then the effectof stress should be less, not greater, than the effect of thedrug itself. They also argued that different neurochemicalmechanisms are involved in stress- and drug-induced rein-statement (Erb, Shaham, & Stewart, 1998; Shaham et al.,1997; Shaham & Stewart, 1996). All in all, we believe thatsensitization, as it is studied in the literature on sensitiza-tion–habituation, provides a simpler and more plausible

explanation for the reinstatement of extinguished drug tak-ing than theories based on retrieval of the memory ofconditioning.

Generalization

Thompson and Spencer (1966) argued that generalizationis a fundamental characteristic of habituation. We did notinclude generalization in the list of characteristics in Table 1because generalization should occur any time stimuli areinvolved. Therefore, finding generalization probably indi-cates only that the effect involves a stimulus and not that itspecifically involves habituation. Nevertheless, consistentwith the current argument, generalization is observed for thephenomena listed earlier. For example, cross-tolerance oc-curs. That is, if an animal develops tolerance to one drug,then it also develops tolerance to other, similar drugs(Cowan, 1981; Herling & Woods, 1981). Cross-primingoccurs. That is, a predose of one drug increases operantresponding for a second drug with similar properties (e.g.,de Wit, 1996; Horger et al., 1990, 1992; Horger, Wellman,Morien, Davies, & Schenk, 1991). Cross-behavioral sensi-tization is observed across similar drugs (e.g., Kalivas &Stewart, 1991). Finally, as just indicated, cross-reinstate-ment may occur (e.g., Schenk & Partridge, 1999).

Conclusions

Summary

We propose a simple model of drug consumption. Wepostulate that drugs are consumed because they serve asreinforcers for any behavior that they follow, including theirown consumption. We also postulate that animals sensitizeand then habituate to the sensory properties of a drug duringits consumption. Consumption terminates when habituationreduces the animal’s responsiveness to the drug and, there-fore, the drug’s effectiveness as a reinforcer. Consumptionresumes after spontaneous recovery restores the ability ofthe drug to once again reinforce its own consumption.Addiction is likely when a drug serves as a particularlystrong reinforcer and when sensitization is strong or habit-uation is weak to that drug.

Advantages of the Current Model

The current model has a number of strengths. To beginwith, it is parsimonious. It postulates only a few processes(sensitization, habituation, reinforcement). These processesare relatively simple and other evidence extensively sup-ports them. The processes are also highly general. Forexample, habituation is observed across so many types ofstimuli and for so many species of animals (e.g., Thorpe,1966) that it seems reasonable to assume that it should occurfor drug stimuli.

The model is compatible with several strongly held as-sumptions in the drug literature. For example, it is wellknown that drugs serve as reinforcers, and it is often as-sumed that drug reinforcers exert their control over behavior


through the same mechanisms that underlie the effective-ness of conventional reinforcers (e.g., Di Chiara & North,1992; Grigson, 2002; Koob, 1992; Nesse & Berridge, 1997;Wise, 1982). Furthermore, as indicated, many have arguedthat drug intake cannot be explained without postulatingboth a depressive process (e.g., habituation) and an activat-ing (e.g., sensitization) process (e.g., Olmstead et al., 2000).

In spite of its simplicity, the model is highly predictivebecause the properties of sensitization and habituation arewell known (e.g., Baker & Tiffany, 1985). In the currentarticle, we demonstrated that drug taking shows at least 10of the properties of sensitization and habituation listed inTable 1 (spontaneous recovery, stimulus specificity, varietyeffects, dishabituation, stimulus rate and exposure effects,long-term habituation, generality, sensitization by initialstimulus presentations, and sensitization by stimuli fromanother modality). In addition, drug taking shows general-ization, a characteristic of habituation listed by Thompsonand Spencer (1966). Such strong empirical similarities seemunlikely to have occurred by chance.

Our argument is strengthened further because several ofthe properties of drug taking that are consistent with themodel are counterintuitive. For example, dishabituation(Characteristic 4, Table 1) and sensitization by stimuli fromother modalities (Characteristic 14, Table 1) both show thatdrug taking may be facilitated by the presentation of extra-neous stimuli. When considering the facilitative effect ofsuch stimuli on eating, Bolles (1980) wrote, “Considertail-pinch as a source of eating. It is an interesting phenom-enon precisely because it does not make much sense; it is anexception to the rule that motivational systems are well-adjusted and independent” (p. 229). In our opinion, the factthat extraneous stimuli facilitate drug taking is also coun-terintuitive. As a result, this evidence provides relativelystrong support for the habituation model that predicts suchan effect.

The model provides insight into characteristics of drugtaking that remain unexplained to date. For example, severalauthors (e.g., Lynch & Carroll, 2001) have wondered whydrug intake stabilizes at relatively constant low levels whenaccess to the drug is restricted to a short, daily session. Incontrast, intake may escalate to levels of toxicity whenanimals are given continuous access to the drug. The currentmodel may help to explain this pattern with the simple andtestable assumption that spontaneous recovery to the drugoccurs faster than the time that usually elapses between theshort sessions of exposure. Habituation occurs with drugintake in both continuous and short sessions. In continuoussessions, drug intake resumes as soon as spontaneous re-covery restores the ability of the drug to act as a reinforcer.In short sessions, the animal cannot resume intake until thenext session. As a result, if spontaneous recovery occursmore quickly than the interval between the short sessions,then the animal may consume more of the drug in thecontinuous- than in the short-session condition. If habitua-tion becomes quicker with successive sessions, as it should(Characteristic 10, Table 1), then these cycles of habituationand spontaneous recovery might also become shorter overtime in a continuous session, yielding an escalating pattern

of drug intake. Such a strong escalating pattern cannotappear in short sessions that are separated by periods spentin the absence of the drug.

The current model also accounts for the evidence thatsupports some other models without encountering theirproblems. For example, as argued, the model provides abetter explanation for reinstatement than retrieval theory(see the Sensitization by Extraneous Stimuli—Reinstatementsection). More important, the current model can explainwhy drug taking appears to be homeostatic without actuallybeing so. Homeostasis is probably the most popular modelof motivated (goal-directed) behavior. According to homeo-static models, a behavior (e.g., eating) is triggered when aphysiological deficit occurs (e.g., blood sugar levels drop).The pursuit of the behavior (e.g., eating) restores the deficit(e.g., blood sugar levels rise) and stops the behavior. Manyauthors have attributed the regulation of drug intake tohomeostasis (e.g., Koob & Bloom, 1988; Poulos & Cappell,1991). For example, Ahmed and Koob (1999) argued thatthere is a set point for drugs similar to that for body weight.Deviations from this set point are detected and corrected tomaintain a constant level of the drug.

In contrast, Ramsay and Woods (1997) argued that drugadministration is a poor area in which to infer homeostaticprocesses. First, homeostatic models provide no explanationfor the activating effects of drugs (see the An ActivatingProcess May Develop With Drug Intake section). Second,drugs often do not occur naturally for a species. As a result,it is hard to imagine how homeostatic processes could havearisen to govern drug taking. Third, even highly biologicallybased processes such as feeding and drinking are not ho-meostatic when they are examined carefully. Feeding anddrinking occur before physiological deficits occur and ter-minate before the deficits are corrected. As a result, Ramsayand Woods argued that it is unlikely that homeostasis isinvolved in drug taking.

The current model accounts for the data that are ex-plained by homeostasis without encountering the problemscited by Ramsay and Woods (1997). According to thecurrent model, the factors that produce spontaneous recov-ery, not the accumulation of a physiological deficit, explainthe increase in a behavior with time since its last pursuit.Habituation, not the correction of a deficit, explains whyperforming a behavior contributes to its termination. Nohomeostatic mechanisms are needed to explain thesefindings.

The current model is also highly predictive (see Table 1).To give one example that has not been discussed, we predictthat preexposure to a small amount of a drug should producesensitization and increase the ability of the drug to serve asa reinforcer. Exposure to larger amounts should producehabituation and decrease the ability of the drug to serve asa reinforcer. That is, a study that varied the size of a predoseof a drug over an appropriate range should observe a rever-sal in the direction of the effect of the preexposure withincreases in the size of the preexposure. We already pre-sented evidence that predoses of a drug may either increase(see the Sensitization by Initial Stimulus Presentation—Priming section) or decrease (see the Stimulus Exposure


section) rate of operant responding for the drug. A study isneeded that directly tests our explanation (differences in thesize of the predose) for these different effects.

Finally, the current model is highly general. It attributesother forms of addiction (e.g., gambling, sex, money,power) to the same mechanisms as drug addiction. Each ofthese other behaviors is supported by a reinforcer. As aresult, the behavior stops when habituation reduces theeffectiveness of that reinforcer, and the behavior resumeswhen spontaneous recovery restores the effectiveness of thereinforcer. Addiction is likely if the reinforcer is particularlystrong and if sensitization to that reinforcer is strong andhabituation is weak (see McSweeney & Swindell, 1999, forfurther details).

Problems With the Current Model

Although the current model has many strengths, it stillsuffers from several problems. First, the model postulatesboth an activating (sensitization) and a depressive (habitu-ation) process. Postulating two, opposing processes givesthe model a great deal of latitude and may make it overlyinclusive. However, postulating both processes does seemnecessary to explain drug taking (e.g., Olmstead et al.,2000). In addition, the current model specifies the condi-tions under which each of these processes occurs. For ex-ample, increases in the effectiveness of drug reinforcersshould occur when only a few stimuli have been presented(sensitization); after the presentation of a strong, different,or extra stimulus (dishabituation); after a change in thenature of the stimulus (violations of stimulus specificity); orwhen the stimulus has not been presented for a time (spon-taneous recovery). Therefore, the current model predictsincreases in the effectiveness of a drug as a reinforcer and,therefore, in drug intake under relatively specific conditions.

Second, the current model is an empirical summary of,rather than a theoretical explanation for, drug intake. Anempirical summary seems necessary at this time because noone theoretical explanation for sensitization and habituationhas been generally accepted. Although many theories havebeen proposed (e.g., Sokolov, 1963; Wagner, 1976), allhave been criticized (e.g., Mackintosh, 1987; Staddon &Higa, 1996). Our argument will be more definitively ac-cepted or rejected only when a theoretical understanding ofsensitization and habituation is provided.

Third, our review provides only a correlational, post hocanalysis of existing data. The current model can only beconfirmed by experiments that are explicitly designed toexamine its predictions. Because the model is highly pre-dictive (see Table 1), however, these experiments should beeasy to carry out. For example, if habituation to ethanolreinforcers contributes to a decline in operant respondingfor those reinforcers (see Figure 1, middle graph), thenpresenting a dishabituator (e.g., a tone) for a brief time (e.g.,5 s) should increase the effectiveness of the ethanol rein-forcers, and response rate should increase. Finding such anoutcome would strongly support the current model becausemost other theories do not obviously make such a prediction

(see Murphy, 2003, for preliminary data on this topic).Table 1 suggests many such tests.

Fourth, some latitude is required to apply the habituationhypothesis to results in the drug literature. For example,when habituation occurs to a neutral stimulus such as alight, some manipulations clearly alter the amount of expo-sure to the light (e.g., its duration), and some clearly alterthe intensity of the light (e.g., its brightness). It is not alwaysas easy to classify manipulations in the drug literature. Forexample, increasing the dosage of a drug might increaseeither drug exposure (Characteristic 8, Table 1) or drugintensity (Characteristic 11, Table 1) or both. The preciseeffect of varying dosage might even differ for differentdrugs. Discovering which effect predominates is importantbecause varying stimulus exposure and stimulus intensitysometimes produce opposite effects (see Table 1).

Although drug taking shows many of the characteristicsof behavior undergoing habituation, these characteristicssometimes seem unusual. For example, we argued thatspontaneous recovery may contribute to the ADE (i.e., toincreases in the intake of alcohol with time of deprivationfor alcohol). However, the deprivation times reported forADE (e.g., 3–28 days) are often longer than the time courseof spontaneous recovery as it is reported in the habituationliterature (e.g., seconds to hours). This difference may beonly one of degree. Alternatively, the current hypothesismay be incorrect or may require refinement. For example,Sinclair and Li (1989) reported a short-term ADE in whichrecovery reaches asymptote between 12 and 24 hr. A re-vised model might argue that spontaneous recovery contrib-utes to this short-term ADE, but an additional process mustbe postulated to explain long-term ADE. Unfortunately,such complexities cannot be evaluated by the data that arepresently available.

In a potentially more important example, sensitizationappears to be stronger for drugs than for most other stimuli.As argued earlier, sensitization may be fleeting and may notoccur for some stimuli studied in the habituation literature(e.g., Groves & Thompson, 1970). In contrast, the findingsthat we attributed to sensitization to drugs (e.g., behavioralsensitization, priming, reinstatement, cross-sensitization be-tween stress and drugs) are robust. This difference mayeventually question the current hypothesis, but it may alsoprovide some insight into why drugs are more frequentlyabused than other stimuli, such as lights and noises. Weargue that drugs are not only highly effective as reinforcersbut that also consuming a small amount of a drug strength-ens the drug’s effectiveness as a reinforcer because sensiti-zation is stronger for drugs than for most other stimuli.

Fifth, the current model alone is an incomplete explana-tion for drug taking. We explain highly complex phenom-ena such as tolerance, behavioral sensitization, and primingwith only a single simple process (habituation or sensitiza-tion). It is unlikely that these phenomena have such simpleand unitary explanations. Although sensitization–habitua-tion may contribute, these processes are unlikely to providea complete explanation for these complex phenomena. Inaddition, sensitization–habituation may play larger roles inthe intake of some drugs than of others.


The current model leaves many questions unanswered.For example, we do not know the exact nature of the stimulito which animals sensitize and habituate when they con-sume drugs. The precise stimuli probably vary from animalto animal and from drug to drug. They may include stimuliassociated with the drug (e.g., its taste, color, texture) anddrug-taking routine (e.g., the sight of a needle). They mayalso include stimuli associated with the subjective, psycho-logical effects of the drug. Nevertheless, this question mustbe answered before precise predictions of the model can betested.

Finally, the model does not provide any explanation formany important findings in the drug literature. For example,our hypothesis does not easily explain how cognitive ma-nipulations can alter the behavioral effect of a drug (e.g.,Marlatt & Rohsenow, 1980; Rohsenow & Marlatt, 1981).For example, analgesic doses of nitrous oxide can becomehyperalgesic after a cognitive manipulation (Ramsay,Brown, & Woods, 1992). Our model does not provide anobvious explanation for the contingent tolerance observedby Poulos and Cappell (1991). They argued that neitheracute nor chronic tolerance can develop unless behavioraldemands are placed on the target system. In contrast, habit-uation develops with exposure to the stimulus, regardless ofwhether a response occurs (e.g., Peeke, 1984; see also Davis& Wagner, 1969). The current hypothesis might be recon-ciled with Poulos and Cappell’s results by arguing thatbehavioral demands make it easier for the animal to detectthe drug, perhaps by adding stimuli to which the animalcould habituate. However, a great deal of research is neededbefore accepting such an argument.

Implications for the Control of Human Drug Intake

Because the current model is highly predictive (see Table1), it has a number of practical implications for the controlof drug taking, many of which are not obviously predictedby other models. According to the current model, drugintake will be weakened by any manipulation that decreasesthe efficacy of the drug as a reinforcer. More specifically,manipulations that decrease sensitization or increase habit-uation to the drug will weaken the ability of that drug toserve as a reinforcer (see Table 1).

Suppose that a person has a problem controlling alcoholintake. In that case, he or she might be encouraged toconsume only one type of alcoholic beverage at a sitting.Consuming several different types of alcohol will slowhabituation and, therefore, extend the intake bout (Charac-teristic 3, Table 1). He or she might be encouraged to drinkonly in a quiet, tranquil environment so that intruding stim-uli will not prolong the drinking through sensitization(Characteristic 14, Table 1). Contrary to the conventionalwisdom, such a drinker should drink alone rather than in acrowd in which others may also provide sensitizing stimuli(Characteristic 14, Table 1). Our drinker should be discour-aged from taking the first sip of alcohol because the first sipwill increase, rather than decrease, the effectiveness ofalcohol as a reinforcer (Characteristic 13, Table 1). Finally,the drinker should not have alcoholic beverages continu-

ously available. As argued earlier, drug consumption ismore likely to escalate when drugs are continuously avail-able than when they are not (see the Advantages of theCurrent Model section). Although these techniques, takenalone, would probably not produce abstinence in an alco-holic, they might help to decrease alcohol intake in thosewith less serious problems.

Our model may also provide a way of predicting theabuse liability of a drug for a particular individual. Drugsthat serve as strong reinforcers should be more likely to beabused than those that serve as weaker reinforcers. Asargued, there are several measures of reinforcer strength.For example, strong reinforcers are preferred to other rein-forcers (e.g., Herrnstein, 1970). In addition, drugs that showstrong sensitization with little or no habituation shouldmaintain their effectiveness longer and, therefore, be moreliable to abuse. The strength and persistence of sensitizationand habituation vary from individual to individual and fromdrug to drug (e.g., Hinde, 1970). Nevertheless, if we arecorrect, then the strength and persistence of sensitizationand habituation for a particular individual to a particulardrug should be measurable by examining the person’s pat-tern of operant responding for that drug. Abuse of a partic-ular drug should be likely if strong sensitization and weakhabituation appear in the temporal pattern of responding forthat drug (see the top graph in Figure 1).

Because many abstinent drug users relapse, understand-ing relapse is thought to be important to controlling drugconsumption. Our model suggests that two important con-tributors to relapse, priming and reinstatement, result fromsensitization. Although the differences in predictions of ourmodel and other models of priming and reinstatement re-main to be specified in detail, some of those implications areclear now. For example, other models (e.g., Siegel, 1975)attribute relapse to the presence of stimuli that have beenassociated with drug taking in the past (e.g., drug parapher-nalia). Our model suggests that any strong stimulus may actas a sensitizer and may, therefore, restore operant respond-ing supported by drugs (e.g., drug consumption). At anyrate, the current model should provide a rich source ofpredictions that may aid in understanding and controllinghuman drug intake.

References

Adams, W. J., Yeh, S. Y., Woods, L. A., & Mitchell, C. L. (1969).Drug-test interaction as a factor in the development of toleranceto the analgesic effect of morphine. Journal of Pharmacologyand Experimental Therapeutics, 168, 251–257.

Ahmed, S. H., & Koob, G. F. (1997). Cocaine- but not food-seeking behavior is reinstated by stress after extinction. Psycho-pharmacology, 132, 289–295.

Ahmed, S. H., & Koob, G. F. (1999). Long-lasting increase in theset point for cocaine self-administration after escalation in rats.Psychopharmacology, 146, 303–312.

Aoyama, K., & McSweeney, F. K. (2001). Habituation may con-tribute to within-session decreases in responding under high-rateschedules of reinforcement. Animal Learning & Behavior, 29,79–91.

Azrin, N. H. (1960, February 26). Sequential effects of punish-ment. Science, 131, 605–606.


Babbini, M., Gaiardi, M., & Bartoletti, M. (1975). Persistence ofchronic morphine effects upon activity in rats 8 months afterceasing the treatment. Neuropharmacology, 14, 611–614.

Baker, T. B., Piper, M. E., McCarthy, D. E., Majeskie, M. R., &Fiore, M. C. (2004). Addiction motivation reformulated: Anaffective processing model of negative reinforcement. Psycho-logical Review, 111, 33–51.

Baker, T. B., & Tiffany, S. T. (1985). Morphine tolerance ashabituation. Psychological Review, 92, 78–108.

Battisti, J. J., Uretsky, N. J., & Wallace, L. J. (1999). Sensitizationof apomorphine-induced stereotyped behavior in mice is con-text-dependent. Psychopharmacology, 146, 42–48.

Baum, W. M. (1974). On two types of deviation from the matchinglaw: Bias and undermatching. Journal of the Experimental Anal-ysis of Behavior, 22, 231–242.

Bell, S. M., Stewart, R. B., Thompson, S. C., & Meisch, R. A.(1997). Food-deprivation increases cocaine-induced condi-tioned place preference and locomotor activity in rats. Psycho-pharmacology, 131, 1–8.

Berridge, K. C., & Robinson, T. E. (2003). Parsing reward. Trendsin Neurosciences, 26, 507–513.

Bigelow, G. E., Griffiths, R. R., & Liebson, I. A. (1977). Pharma-cological influences upon human ethanol self-administration. InM. M. Gross (Ed.), Alcohol intoxication and withdrawal (pp.523–538). New York: Plenum Press.

Bolles, R. C. (1980). Stress-induced overeating? A response toRobbins and Fray. Appetite, 1, 229–230.

Bouton, M. E. (1993). Context, time, and memory retrieval in theinterference paradigms of Pavlovian learning. PsychologicalBulletin, 114, 80–99.

Broster, B. S., & Rankin, C. H. (1994). Effects of changinginterstimulus interval during habituation in Caenorhabditis el-egans. Behavioral Neuroscience, 108, 1019–1029.

Buczek, Y., Le, A. D., Wang, A., Stewart, J., & Shaham, Y.(1999). Stress reinstates nicotine seeking but not sucrose solu-tion seeking in rats. Psychopharmacology, 144, 183–188.

Cabeza de Vaca, S., & Carr, K. D. (1998). Food restrictionenhances the central rewarding effect of abused drugs. Journalof Neuroscience, 18, 7502–7510.

Caggiula, A. R., Antelman, S. M., Aul, E., Knopf, S., & Edwards,D. J. (1989). Prior stress attenuates the analgesic response butsensitizes the corticosterone and cortical dopamine responses tostress 10 days later. Psychopharmacology, 99, 233–237.

Campbell, B. A., & Fibiger, H. C. (1971, October 8). Potentiationof amphetamine-induced arousal by starvation. Nature, 233,424–425.

Carew, T. J. (1984). An introduction to cellular approaches used inthe analysis of habituation and sensitization in Aplysia. InH. V. S. Peeke & L. Petrinovich (Eds.), Habituation, sensitiza-tion, and behavior (pp. 205–249). New York: Academic Press.

Carr, K. D., Kim, G.-Y., & Cabeza de Vaca, S. (2000). Chronicfood restriction in rats augments the central rewarding effect ofcocaine and the delta 1 opioid agonist, DPDPE, but not thedelta 2 agonist, deltorphin-II. Psychopharmacology, 152, 200–207.

Carr, K. D., Kim, G.-Y., & Cabeza de Vaca, S. (2001). Rewardingand locomotor-activating effects of direct dopamine receptoragonists are augmented by chronic food restriction in rats.Psychopharmacology, 154, 420–428.

Carroll, M. E. (1985). The role of food deprivation in the main-tenance and reinstatement of cocaine-seeking behavior in rats.Drug & Alcohol Dependence, 16, 95–109.

Carroll, M. E., & Meisch, R. A. (1984). Increased drug-reinforcedbehavior due to food deprivation. Advances in Behavioral Phar-macology, 4, 47–88.

Cepeda-Benito, A., & Tiffany, S. T. (1996). Test-specific mani-festations of associative tolerance to the analgesic effects ofmorphine in the rat. Psychobiology, 24, 327–332.

Cepeda-Benito, A., Tiffany, S. T., & Cox, L. S. (1999). Context-specific morphine tolerance on the paw-pressure and tail-shockvocalization tests: Evidence of associative tolerance withoutconditioned compensatory responding. Psychopharmacology,145, 426–432.

Chan, A. W. K. (1991). Multiple drug use in drug and alcoholaddiction. In N. S. Miller (Ed.), Comprehensive handbook ofdrug and alcohol addiction (pp. 87–113). New York: MarcelDekker.

Chen, C.-S. (1979). Acquisition of behavioral tolerance to ethanolas a function of reinforced practice in rats. Psychopharmacol-ogy, 63, 285–288.

Chiamulera, C., Borgo, C., Falchetto, S., Valerio, E., & Tessari, M.(1996). Nicotine reinstatement of nicotine self-administrationafter long-term extinction. Psychopharmacology, 127, 102–107.

Chutuape, M. A. D., Mitchell, S. H., & de Wit, H. (1994). Ethanolpreloads increase ethanol preference under concurrent random-ratio schedules in social drinkers. Experimental and ClinicalPsychopharmacology, 2, 310–318.

Comer, S. D., Lac, S. T., Wyvell, C. L., Curtis, L. K., & Carroll,M. E. (1995). Food deprivation affects extinction and reinstate-ment of responding in rats. Psychopharmacology, 121, 150–157.

Conrod, P. J., Peterson, J. B., & Pihl, R. O. (1997). Disinhibitedpersonality and sensitivity to alcohol reinforcement: Indepen-dent correlates of drinking behavior in sons of alcoholics. Al-coholism: Clinical and Experimental Research, 21, 1320–1332.

Conrod, P. J., Peterson, J. B., & Pihl, R. O. (2001). Reliability andvalidity of alcohol-induced heart rate increase as a measure ofsensitivity to the stimulant properties of alcohol. Psychophar-macology, 157, 20–30.

Conrod, P. J., Pihl, R. O., & Ditto, B. (1995). Autonomic reactivityand alcohol-induced dampening in men at risk for alcoholismand men at risk for hypertension. Alcoholism: Clinical andExperimental Research, 19, 482–489.

Conrod, P. J., Pihl, R. O., & Vassileva, J. (1998). Differentialsensitivity to alcohol reinforcement in groups of men at risk fordistinct alcoholism subtypes. Alcoholism: Clinical and Experi-mental Research, 22, 585–597.

Cowan, A. (1981). Simple in vitro tests that differentiate prototypeagonists at opiate receptors. Life Sciences, 28, 1559–1570.

Crowell, C. R., Hinson, R. E., & Siegel, S. (1981). The role ofconditional drug responses in tolerance to the hypothermiceffects of ethanol. Psychopharmacology, 73, 51–54.

Cunningham, C. L., Niehus, D. R., Malott, D. H., & Prather, L. K.(1992). Genetic differences in the rewarding and activatingeffects of morphine and ethanol. Psychopharmacology, 107,385–393.

Dafters, R., Hetherington, M., & McCartney, H. (1983). Blockingand sensory preconditioning effects in morphine analgesic tol-erance: Support for a Pavlovian conditioning model of drugtolerance. Quarterly Journal of Experimental Psychology: Com-parative and Physiological Psychology, 35, 1–11.

Davis, M., & Wagner, A. R. (1969). Habituation of startle responseunder incremental sequence of stimulus intensities. Journal ofComparative and Physiological Psychology, 67, 486–492.

Delameter, A. R., & LoLordo, V. M. (1991). Event revaluationprocedures and associative structures in Pavlovian conditioning.


In L. Dachowski & C. F. Flaherty (Eds.), Current topics inanimal learning: Brain, emotion, and cognition (pp. 55–94).Hillsdale, NJ: Erlbaum.

Deminiere, J. M., Piazza, P. V., Guegan, G., Abrous, N., Maccari,S., Le Moal, M., & Simon, H. (1992). Increased locomotorresponse to novelty and propensity to intravenous amphetamineself-administration in adult offspring of stressed mothers. BrainResearch, 586, 135–139.

Deroche, V., Piazza, P. V., Casolini, P., Le Moal, M., & Simon, H.(1993). Sensitization to the psychomotor effects of amphet-amine and morphine induced by food restriction depends oncorticosterone secretion. Brain Research, 611, 352–356.

Deroche, V., Piazza, P. V., Casolini, P., Maccari, S., Le Moal, M.,& Simon, H. (1992). Stress-induced sensitization to amphet-amine and morphine psychomotor effects depend on stress-induced corticosterone secretion. Brain Research, 598, 343–348.

De Vries, T. J., Schoffelmeer, A. N. M., Binnekade, R., & Vander-schuren, L. J. M. J. (1999). Dopaminergic mechanisms mediat-ing the incentive to seek cocaine and heroin following long-termwithdrawal of IV drug self-administration. Psychopharmacol-ogy, 143, 254–260.

de Wit, H. (1996). Priming effects with drugs and other reinforc-ers. Experimental and Clinical Psychopharmacology, 4, 5–10.

de Wit, H., & Chutuape, M. A. (1993). Increased ethanol choice insocial drinkers following ethanol preload. Behavioural Pharma-cology, 4, 29–36.

de Wit, H., Pierri, J., & Johanson, C. E. (1989). Assessing indi-vidual differences in ethanol preference using a cumulativedosing procedure. Psychopharmacology, 98, 113–119.

de Wit, H., & Stewart, J. (1981). Reinstatement of cocaine-rein-forced responding in the rat. Psychopharmacology, 75, 134–143.

de Wit, H., & Stewart, J. (1983). Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology, 79, 29–31.

de Wit, H., Uhlenhuth, E. H., Pierri, J., & Johanson, C. E. (1987).Individual differences in behavioral and subjective responses toalcohol. Alcoholism: Clinical and Experimental Research, 11,52–59.

Di Chiara, G., Acquas, E., & Carboni, E. (1992). Drug motivationand abuse: A neurobiological perspective. In P. W. Kalivas &H. H. Samson (Eds.), The neurobiology of drug and alcoholaddiction (pp. 207–219). New York: New York Academy ofSciences.

Di Chiara, G., & North, R. A. (1992). Neurobiology of opiateabuse. Trends in Pharmacological Sciences, 13, 185–193.

Domino, E. F., Vasko, M. R., & Wilson, A. E. (1976). Mixeddepressant and stimulant actions of morphine and their relation-ship to brain acetylcholine. Life Sciences, 18, 361–376.

Duvauchelle, C. L., Sapoznik, T., & Kornetsky, C. (1998). Thesynergistic effects of combining cocaine and heroin (“speed-ball”) using a progressive-ratio schedule of drug reinforcement.Pharmacology, Biochemistry, and Behavior, 61, 297–302.

Epstein, L. H., Caggiula, A. R., Perkins, K. A., Mitchell, S. L., &Rodefer, J. S. (1992). Abstinence from smoking decreases ha-bituation to food cues. Physiology & Behavior, 52, 641–646.

Epstein, L. H., Rodefer, J. S., Wisniewski, L., & Caggiula, A. R.(1992). Habituation and dishabituation of human salivary re-sponse. Physiology & Behavior, 51, 945–950.

Erb, S., Shaham, Y., & Stewart, J. (1996). Stress reinstates co-caine-seeking behavior after prolonged extinction and a drug-free period. Psychopharmacology, 128, 408–412.

Erb, S., Shaham, Y., & Stewart, J. (1998). The role of cortico-tropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats. Journal of Neuro-science, 18, 5529–5536.

Fadda, F., & Rossetti, Z. L. (1998). Chronic ethanol consumption:From neuroadaptation to neurodegeneration. Progress in Neu-robiology, 56, 385–431.

Finn, P. R., & Pihl, R. O. (1988). Risk for alcoholism: A compar-ison between two different groups of sons of alcoholics oncardiovascular reactivity and sensitivity to alcohol. Alcohol:Clinical and Experimental Research, 12, 742–747.

Finn, P. R., Zeitouni, N. C., & Pihl, R. O. (1990). Effects ofalcohol on psychophysiological hyperreactivity to nonaversiveand aversive stimuli in men at high risk for alcoholism. Journalof Abnormal Psychology, 99, 79–85.

Fowles, D. C. (1983). Appetitive motivational influences on heartrate. Personality and Individual Differences, 4, 393–401.

Gabrielli, W. F., Nagoshi, C. T., Rhea, S. A., & Wilson, J. R.(1991). Anticipated and subjective sensitivities to alcohol. Jour-nal on the Study of Alcohol, 52, 205–214.

Geier, A., Mucha, R. F., & Pauli, P. (2000). Appetitive nature ofdrug cues confirmed with physiological measures in a modelusing pictures of smoking. Psychopharmacology, 150, 283–291.

Gerber, G. J., Bozarth, M. A., Spindler, J. E., & Wise, R. A.(1985). Concurrent heroin self-administration and intracranialself-stimulation in rats. Pharmacology, Biochemistry, and Be-havior, 23, 837–842.

Glick, S. D., Shapiro, R. M., Drew, K. L., Hinds, P. A., & Carlson,J. N. (1986). Differences in spontaneous and amphetamine-induced rotational behavior and in sensitization to amphetamineamong Sprague–Dawley derived rats from different sources.Physiology & Behavior, 38, 67–70.

Goeders, N. E., & Guerin, G. F. (1994). Noncontingent electricfoot shock facilitates the acquisition of intravenous cocaineself-administration in rats. Psychopharmacology, 114, 63–70.

Grahame, N. J., Rodd-Henricks, K., Li, T.-K., & Lumeng, L.(2000). Ethanol locomotor sensitization, but not tolerance, cor-relates with selection for alcohol preference in high- and low-alcohol preferring mice. Psychopharmacology, 151, 252–260.

Green, T. A., Phillips, S. B., Crooks, P. A., Dwoskin, L. P., &Bardo, M. T. (2000). Nornicotine pretreatment decreases intra-venous nicotine self-administration in rats. Psychopharmacol-ogy, 152, 289–294.

Grigson, P. S. (2002). Like drugs for chocolate: Separate rewardsmodulated by common mechanisms? Physiology & Behav-ior, 76, 345–346.

Groves, P. M., & Thompson, R. F. (1970). Habituation: A dual-process theory. Psychological Review, 77, 419–450.

Hadaway, P. F., Alexander, B. K., Coambs, R. B., & Beyerstein,B. (1979). The effect of housing and gender on preferences formorphine-sucrose solutions in rats. Psychopharmacology, 66,87–91.

Haney, M., Maccari, S., Le Moal, M., Simon, H., & Piazza, P. V.(1995). Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Research, 698,46–52.

Harris, J. D. (1943). Habituatory response decrement in the intactorganism. Psychological Bulletin, 40, 385–422.

Herling, S., & Woods, J. H. (1981). Discriminative stimulus ef-fects of narcotics: Evidence for multiple receptor-mediated ac-tions. Life Sciences, 28, 1571–1584.

Herrnstein, R. J. (1970). On the law of effect. Journal of theExperimental Analysis of Behavior, 13, 243–266.


Heyser, C. J., Schulteis, G., & Koob, G. F. (1997). Increasedethanol self-administration after a period of imposed ethanoldeprivation in rats trained in a limited access paradigm. Alco-holism: Clinical and Experimental Research, 21, 784–791.

Hinde, R. A. (1970). Behavioral habituation. In G. Horn & R. A.Hinde (Eds.), Short-term changes in neural activity and behav-ior (pp. 3–40). Cambridge, England: Cambridge UniversityPress.

Hinson, R. E., & Poulos, C. X. (1981). Sensitization to the behav-ioral effects of cocaine: Modification by Pavlovian conditioning.Pharmacology, Biochemistry, and Behavior, 15, 559–562.

Hinson, R. E., & Siegel, S. (1980). The contribution of Pavlovianconditioning to ethanol tolerance dependence. In H. Rigter &J. C. Crabbe, Jr. (Eds.), Alcohol tolerance, dependence, andaddiction (pp. 181–199). Amsterdam, the Netherlands: Elsevier.

Holdstock, L., King, A. C., & de Wit, H. (2000). Subjective andobjective responses to ethanol in moderate/heavy and lightsocial drinkers. Alcoholism: Clinical and Experimental Re-search, 24, 789–794.

Horger, B. A., Giles, M. K., & Schenk, S. (1992). Preexposure toamphetamine and nicotine predisposes rats to self-administer alow dose of cocaine. Psychopharmacology, 107, 271–276.

Horger, B. A., Shelton, K., & Schenk, S. (1990). Preexposuresensitizes rats to the rewarding effects of cocaine. Pharmacol-ogy, Biochemistry, and Behavior, 37, 707–711.

Horger, B. A., Wellman, P. J., Morien, A., Davies, B. T., &Schenk, S. (1991). Caffeine exposure sensitizes rats to thereinforcing effects of cocaine. Neuroreport, 2, 53–56.

Jerome, E. A., Moody, J. A., Connor, T. J., & Ryan, J. (1958).Intensity of illumination and the rate of responding in a multi-ple-door situation. Journal of Comparative and PhysiologicalPsychology, 51, 47–49.

Jones, G. H., Marsden, C. A., & Robbins, T. W. (1990). Increasedsensitivity to amphetamine and reward-related stimuli followingsocial isolation in rats: Possible disruption of dopamine-depen-dent mechanisms of the nucleus accumbens. Psychopharmacol-ogy, 102, 364–372.

Kalant, H., LeBlanc, A. E., & Gibbins, R. J. (1971). Tolerance to,and dependence on, some non-opiate psychotropic drugs. Phar-macological Reviews, 23, 135–191.

Kalivas, P. W., & Duffy, P. (1989). Similar effects of daily cocaineand stress on mesocorticolimbic dopamine neurotransmission inthe rat. Biological Psychiatry, 25, 913–928.

Kalivas, P. W., Duffy, P., Abhold, R., & Dilts, R. P. (1988).Sensitization of mesolimbic dopamine neurons by neuropep-tides and stress. In P. W. Kalivas & C. D. Barnes (Eds.),Sensitization in the nervous system (pp. 119–144). Caldwell,NJ: Telford Press.

Kalivas, P. W., & Stewart, J. (1991). Dopamine transmission in theinitiation and expression of drug- and stress-induced sensitiza-tion of motor activity. Brain Research Reviews, 16, 223–244.

Kandel, E. R., Schwartz, J. H., & Jessel, T. M. (2000). Principlesof neural science (4th ed.). New York: McGraw-Hill.

Kayan, S., Woods, L. A., & Mitchell, C. L. (1969). Experience asa factor in the development of tolerance to the analgesic effectof morphine. European Journal of Pharmacology, 6, 333–339.

Kesner, R. P., & Baker, T. B. (1981). A two-process model ofopiate tolerance. In J. L. Martinez, R. A. Jensen, R. B. Messing,H. Rigter, & J. L. McGaugh (Eds.), Endogenous peptides andlearning and memory processes (pp. 479–518). New York:Academic Press.

Koob, G. F. (1992). Drugs of abuse: Anatomy, pharmacology andfunction of reward pathways. Trends in Pharmacological Sci-ence, 13, 177–184.

Koob, G. F., & Bloom, F. E. (1988, November 4). Cellular andmolecular mechanisms of drug dependence. Science, 242, 715–723.

Kornetsky, C., & Bain, G. (1968, November 29). Morphine: Sin-gle-dose tolerance. Science, 162, 1011–1012.

Le, A. D., Quan, B., Juzytch, W., Fletcher, P. J., Joharchi, N., &Shaham, Y. (1998). Reinstatement of alcohol seeking by prim-ing injections of alcohol and exposure to stress in rats. Psycho-pharmacology, 135, 169–174.

Leibrecht, B. C., & Askew, H. R. (1969). Habituation of thehead-shake response in the rat: Recovery, transfer, and changesin topography. Journal of Comparative and Physiological Psy-chology, 69, 699–708.

Leyton, M., & Stewart, J. (1990). Preexposure to foot-shock sen-sitizes the locomotor response to subsequent systemic morphineand intra-nucleus accumbens amphetamine. Pharmacology,Biochemistry, and Behavior, 37, 303–310.

Li, T.-K., & Lumeng, L. (1984). Alcohol preference and voluntaryalcohol intakes of inbred rat strains and the National Institutes ofHealth heterogeneous stock of rats. Alcoholism: Clinical andExperimental Research, 8, 485–486.

Li, T.-K., Spanagel, R., Colombo, G., McBride, W. J., Porrino,L. J., Suzuki, T., & Rodd-Henricks, Z. A. (2001). Alcoholreinforcement and voluntary ethanol consumption. Alcoholism:Clinical and Experimental Research, 25, 117S–126S.

Little, H. J., Butterworth, A. R., O’Callaghan, M. J., Wilson, J.,Cole, J., & Watson, W. P. (1999). Low alcohol preferenceamong the “high alcohol preference” C57 strain of mice; pref-erence increased by saline injections. Psychopharmacology,147, 182–189.

Lu, L., Shepard, J. D., Hall, F. S., & Shaham, Y. (2003). Effect ofenvironmental stressors on opiate and psychostimulant rein-forcement, reinstatement, and discrimination in rats: A review.Neuroscience and Biobehavioral Reviews, 27, 457–491.

Ludwig, A. M., & Wikler, A. (1974). “Craving” and relapse todrink. Quarterly Journal of Studies on Alcohol, 35, 108–130.

Ludwig, A. M., Wikler, A., & Stark, L. H. (1974). The first drink:Psychobiological aspects of craving. Archives of General Psy-chiatry, 30, 539–547.

Lynch, W. J., & Carroll, M. E. (2001). Regulation of drug intake.Experimental and Clinical Psychopharmacology, 9, 131–143.

Mackintosh, N. J. (1987). Neurobiology, psychology, and habitu-ation. Behaviour Research and Therapy, 25, 81–97.

Marcus, E. A., Nolen, T. G., Rankin, C. H., & Carew, T. J. (1988,July 8). Behavioral dissociation of dishabituation, sensitization,and inhibition in Aplysia. Science, 241, 210–213.

Marlatt, G. A., & Rohsenow, D. (1980). Cognitive processes inalcohol use: Expectancy and the balanced placebo design. InN. K. Mello (Ed.), Advances in substance abuse (pp. 155–199).New York: JAI Press.

Martin, C. S., & Moss, H. B. (1993). Measurement of acutetolerance to alcohol in human subjects. Alcoholism: Clinical andExperimental Research, 17, 211–216.

Martin-Iverson, M. T., Iversen, S. D., & Stahl, S. M. (1988).Long-term motor stimulant effects of (�)-4-propyl-9-hy-droxynapthoxazine (PHNO), a dopamine D2 receptor agonist:Interactions with a dopamine D1 receptor antagonist and ago-nist. European Journal of Pharmacology, 149, 25–31.

Martin-Iverson, M. T., Stahl, S. M., & Iversen, S. D. (1988).Chronic administration of a selective dopamine D2 agonist:Factors determining behavioral tolerance and sensitization. Psy-chopharmacology, 95, 534–539.


Masur, J., & Boerngen, R. (1980). The excitatory component ofethanol in mice: A chronic study. Pharmacology, Biochemistry,and Behavior, 13, 777–780.

Matsuzawa, S., Suzuki, T., & Misawa, M. (1998). Conditionedfear stress induces ethanol-associated place preference in rats.European Journal of Pharmacology, 341, 127–130.

McKinzie, D. L., Nowak, K. L., Yorger, L., McBride, W. J.,Murphy, J. M., Lumeng, L., & Li, T.-K. (1998). The alcoholdeprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions. Alcoholism: Clinicaland Experimental Research, 22, 1170–1176.

McSweeney, F. K. (1992). Rate of reinforcement and sessionduration as determinants of within-session patterns of respond-ing. Animal Learning & Behavior, 20, 160–169.

McSweeney, F. K., Hinson, J. M., & Cannon, C. B. (1996).Sensitization–habituation may occur during operant condition-ing. Psychological Bulletin, 120, 256–271.

McSweeney, F. K., & Murphy, E. S. (2000). Criticisms of thesatiety hypothesis as an explanation for within-session decreasesin responding. Journal of the Experimental Analysis of Behav-ior, 74, 347–361.

McSweeney, F. K., & Roll, J. M. (1993). Responding changessystematically within sessions during conditioning procedures.Journal of the Experimental Analysis of Behavior, 60, 621–640.

McSweeney, F. K., & Roll, J. M. (1998). Do animals satiate orhabituate to repeatedly presented reinforcers? Psychonomic Bul-letin & Review, 5, 428–442.

McSweeney, F. K., & Swindell, S. (1999). General-process theo-ries of motivation revisited: The role of habituation. Psycholog-ical Bulletin, 125, 437–457.

McSweeney, F. K., Weatherly, J. N., & Swindell, S. (1996).Reinforcer value may change within experimental sessions.Psychonomic Bulletin & Review, 3, 372–375.

Meisch, R. A., & Lemaire, G. A. (1990). Reinforcing effects of apentobarbital-ethanol combination relative to each drug alone.Pharmacology, Biochemistry, and Behavior, 35, 443–450.

Meisch, R. A., & Thompson, T. (1974). Ethanol intake as afunction of concentration during food deprivation and satiation.Pharmacology, Biochemistry, and Behavior, 2, 589–596.

Mello, N. K., & Mendelson, J. H. (1972). Drinking patterns duringwork-contingent and noncontingent alcohol acquisition. Psy-chosomatic Medicine, 34, 139–164.

Mello, N. K., Negus, S. S., Lukas, S. E., Mendelson, J. H., Sholar,J. W., & Drieze, J. (1995). A primate model of polydrug abuse:Cocaine and heroin combinations. Journal of Pharmacologyand Experimental Therapeutics, 274, 1325–1337.

Mendrek, A., Blaha, C. D., & Phillips, A. G. (1998). Pre-exposureof rats to amphetamine sensitizes self-administration of thisdrug under a progressive ratio schedule. Psychopharmacology,135, 416–422.

Miczek, K. A., & Mutschler, N. H. (1996). Activational effects ofsocial stress on IV cocaine self-administration in rats. Psycho-pharmacology, 128, 256–264.

Miller, H. L. (1976). Matching-based hedonic scaling in the pi-geon. Journal of the Experimental Analysis of Behavior, 26,335–347.

Mook, D. G. (1996). Motivation: The organization of action (2nded.). New York: Norton.

Morgan, D., Brebner, K., Lynch, W. J., & Roberts, D. C. S. (2002).Increases in the reinforcing efficacy of cocaine after particularhistories of reinforcement. Behavioural Pharmacology, 13,389–396.

Morgan, M. J. (1974). Resistance to satiation. Animal Behav-iour, 22, 449–466.

Mucha, R. F., Geier, A., & Pauli, P. (1999). Modulation of cravingby cues having differential overlap with pharmacological effect:Evidence for cue approach in smokers and social drinkers.Psychopharmacology, 147, 306–313.

Murphy, E. S. (2003). Dynamic changes in the value of ethanolreinforcers. Unpublished doctoral dissertation, WashingtonState University, Pullman.

Mushlin, B. E., Grell, R., & Cochin, J. (1976). Studies of toler-ance: I. The role of the interval between doses on the develop-ment of tolerance to morphine. Journal of Pharmacology andExperimental Therapeutics, 196, 280–287.

Nesse, R. M., & Berridge, K. C. (1997, October 3). Psychoactivedrug use in evolutionary perspective. Science, 278, 63–66.

Newlin, D. B., & Thomson, J. B. (1990). Alcohol challenge withsons of alcoholics: A critical review and analysis. PsychologicalBulletin, 108, 383–402.

Newlin, D. B., & Thomson, J. B. (1991). Chronic tolerance andsensitization to alcohol in sons of alcoholics. Alcoholism: Clin-ical and Experimental Research, 15, 399–405.

Newlin, D. B., & Thomson, J. B. (1999). Chronic tolerance andsensitization to alcohol in sons of alcoholics: II. Replication andreanalysis. Experimental and Clinical Psychopharmacology, 7,234–243.

Nowak, K. L., McKinzie, D. L., McBride, W. J., & Murphy, J. M.(1999). Patterns of ethanol and saccharin intake in P rats underlimited-access conditions. Alcohol, 19, 85–96.

Numan, R. (1981). Multiple exposures to ethanol facilitate intra-venous self-administration of ethanol by rats. Pharmacology,Biochemistry, and Behavior, 15, 101–108.

Olmstead, M. C., Parkinson, J. A., Miles, F. J., Everitt, B. J., &Dickinson, A. (2000). Cocaine seeking by rats: Regulation,reinforcement, and activation. Psychopharmacology, 152, 123–131.

Paletta, M. S., & Wagner, A. R. (1986). Development of context-specific tolerance to morphine: Support for a dual-process in-terpretation. Behavioral Neuroscience, 100, 611–623.

Pavlov, I. P. (1927). Conditioned reflexes. New York: Dover.Peeke, H. V. S. (1984). Habituation and the maintenance of terri-

torial boundaries. In H. V. S. Peeke & L. Petrinovich (Eds.),Habituation, sensitization, and behavior (pp. 393–421). NewYork: Academic Press.

Peeke, H. V. S., & Peeke, S. C. (1973). Habituation in fish withspecial reference to intraspecific aggressive behavior. InH. V. S. Peeke & M. J. Herz (Eds.), Habituation: Behavioralstudies (Vol. 1, pp. 59–83). New York: Academic Press.

Peeke, H. V. S., & Veno, A. (1973). Stimulus specificity ofhabituated aggression in the stickleback (Gasterosteus aculea-tus). Behavioral Biology, 8, 427–432.

Pert, A., Post, R. M., & Weiss, S. R. B. (1990). Conditioning as acritical determinant of sensitization induced by psychomotorstimulants. NIDA Research Monograph, 97, 208–241.

Peterson, J. B., Pihl, R. O., Gianoulakis, C., Conrod, P. J., Finn,P. R., Stewart, S. H., et al. (1996). Ethanol-induced change incardiac and endogenous opiate function and risk for alcoholism.Alcoholism: Clinical and Experimental Research, 20, 1542–1552.

Piazza, P. V., Deminiere, J. M., Le Moal, M., & Simon, H. (1989,September 29). Factors that predict individual vulnerability toamphetamine self-administration. Science, 245, 1511–1513.

Piazza, P. V., Deminiere, J. M., Le Moal, M., & Simon, H. (1990).Stress- and pharmacologically induced behavioral sensitizationincreases vulnerability to acquisition of amphetamine self-ad-ministration. Brain Research, 514, 22–26.


Piazza, P. V., & Le Moal, M. (1996). Pathophysiological basis ofvulnerability to drug abuse: Role of an interaction betweenstress, glucocorticoids, and dopamine neurons. Annual Reviewof Pharmacology and Toxicology, 36, 359–378.

Piazza, P. V., & Le Moal, M. (1998). The role of stress in drugself-administration. Trends in Pharmacological Sciences, 19,67–74.

Pinel, J. P. J., & Puttaswamaiah, S. (1985). Tolerance to alcohol’santiconvulsant effect is not under Pavlovian control. Pharma-cology, Biochemistry, and Behavior, 23, 959–964.

Pinsker, H. M., Hening, W. A., Carew, T. J., & Kandel, E. R.(1973, December 7). Long-term sensitization of a defensivewithdrawal reflex in Aplysia. Science, 182, 1039–1042.

Post, R. M., & Rose, H. (1976, April 22). Increasing effects ofrepetitive cocaine administration in the rat. Nature, 260, 731–732.

Post, R. M., Weiss, S. R. B., & Pert, A. (1987). The role of contextand conditioning in behavioral sensitization to cocaine. Psycho-pharmacology Bulletin, 23, 425–429.

Poucet, B., Durup, M., & Thinus-Blanc, C. (1988). Short-term andlong-term habituation of exploration in rats, hamsters, and ger-bils. Behavioural Processes, 16, 203–211.

Poulos, C. X., & Cappell, H. (1991). Homeostatic theory of drugtolerance: A general model of physiological adaptation. Psycho-logical Review, 98, 390–408.

Poulos, C. X., Hunt, T., & Cappell, H. (1988). Tolerance tomorphine analgesia is reduced by the novel addition or omissionof an alcohol cue. Psychopharmacology, 94, 412–416.

Rachlin, H. (1973). Contrast and matching. Psychological Re-view, 80, 217–234.

Ramsay, D. S., Brown, A. C., & Woods, S. C. (1992). Acutetolerance to nitrous oxide in humans. Pain, 51, 367–373.

Ramsay, D. S., & Woods, S. C. (1997). Biological consequencesof drug administration: Implications for acute and chronic tol-erance. Psychological Review, 104, 170–193.

Ramsey, N. F., & Van Ree, J. M. (1993). Emotional but notphysical stress enhances intravenous cocaine self-administrationin drug-naı̈ve rats. Brain Research, 608, 216–222.

Ranaldi, R., & Munn, E. (1998). Polydrug self-administration inrats: Cocaine–heroin is more rewarding than cocaine alone.Neuroreport, 9, 2463–2466.

Rescorla, R. A., & Heth, D. C. (1975). Reinstatement of fear to anextinguished conditioned stimulus. Journal of ExperimentalPsychology: Animal Behavior Processes, 1, 88–96.

Robinson, T. E. (1988). Stimulant drugs and stress: Factors influ-encing individual differences in the susceptibility to sensitiza-tion. In P. W. Kalivas & C. Barnes (Eds.), Sensitization of thenervous system (pp. 145–173). Caldwell, NJ: Telford Press.

Robinson, T. E., & Becker, J. B. (1986). Enduring changes in brainand behavior produced by chronic amphetamine administration:A review and evaluation of animal models of amphetaminepsychosis. Brain Research Reviews, 11, 157–198.

Robinson, T. E., & Berridge, K. C. (1993). The neural basis ofdrug craving: An incentive-sensitization theory of addiction.Brain Research Reviews, 18, 247–291.

Robinson, T. E., & Berridge, K. C. (2001). Incentive-sensitizationand addiction. Addiction, 96, 103–114.

Rodd-Henricks, Z. A., McKinzie, D. L., Crile, R. S., Murphy,J. M., & McBride, W. J. (2000). Regional heterogeneity for theintracranial self-administration of ethanol within the ventraltegmental area of female Wistar rats. Psychopharmacology,149, 217–224.

Rohsenow, D. J., & Marlatt, G. A. (1981). The balanced placebodesign: Methodological considerations. Addictive Behaviors, 6,107–122.

Rush, C. R., Sullivan, J. T., & Griffiths, R. R. (1995). Intravenouscaffeine in stimulant drug abusers: Subjective reports and phys-iological effects. Journal of Pharmacology and ExperimentalTherapeutics, 273, 351–358.

Ruzich, M., & Martin-Iverson, M. T. (2000). Pinealectomy blocksstress-induced motor stimulation but not sensitization and tol-erance to dopamine D2 receptor agonist. Psychopharmacology,152, 275–282.

Samson, H. H., & Chappell, A. (2001). Effects of alcohol depri-vation on alcohol consumption using a sipper-tube procedure.Alcoholism: Clinical and Experimental Research, 25, 680–686.

Sayette, M. A., Martin, C. S., Wertz, J. M., Shiffman, S., & Perrot,M. A. (2001). A multi-dimensional analysis of cue-elicitedcraving in heavy smokers and tobacco chippers. Addiction, 96,1419–1432.

Schenk, S., & Davidson, E. S. (1998). Stimulant preexposuresensitizes rats and humans to the rewarding effects of cocaine.NIDA Research Monographs, 169, 56–82.

Schenk, S., Lacelle, G., Gorman, K., & Amit, Z. (1987). Cocaineself-administration in rats influenced by environmental condi-tions: Implications for the etiology of drug abuse. NeuroscienceLetters, 81, 227–231.

Schenk, S., & Partridge, B. (1999). Cocaine-seeking produced byexperimenter-administered drug injections: Dose-effect rela-tionships in rats. Psychopharmacology, 147, 285–290.

Schenk, S., Partridge, B., & Shippenberg, T. S. (2000). Reinstate-ment of extinguished drug-taking behavior in rats: Effect ofkappa-opioid receptor agonist, U69593. Psychopharmacology,151, 85–90.

Schenk, S., Worley, C. M., McNamara, C., & Valadez, A. (1996).Acute and repeated exposure to caffeine: Effects on reinstate-ment of extinguished cocaine-taking behavior in rats. Psycho-pharmacology, 126, 17–23.

Schuster, C. R., Dockens, W. S., & Woods, J. H. (1966). Behav-ioral variables affecting the development of amphetamine tol-erance. Psychopharmacologia, 9, 170–182.

Schuster, C. R., & Thompson, T. (1969). Self-administration ofand behavioral dependence on drugs. Annual Review of Phar-macology, 9, 483–502.

Seaman, S. F. (1985). Growth of morphine tolerance: The effect ofdose and interval between doses. In F. R. Brush & J. B. Over-mier (Eds.), Affect, conditioning, and cognition: Essays on thedeterminants of behavior (pp. 249–262). Hillsdale, NJ:Erlbaum.

Segal, D. S., & Kuczenski, R. (1987). Individual differences inresponsiveness to single and repeated amphetamine administra-tion: Behavioral characteristics and neurochemical correlates.Journal of Pharmacology and Experimental Therapeutics, 242,917–926.

Segal, D. S., & Kuczenski, R. (1992). In vivo microdialysis revealsa diminished amphetamine-induced DA response correspondingto behavioral sensitization produced by repeated amphetaminepretreatment. Brain Research, 571, 330–337.

Shaham, Y. (1993). Immobilization stress-induced oral opioidself-administration and withdrawal in rats: Role of conditioningfactors and the effect of stress on “relapse” to opioid drugs.Psychopharmacology, 111, 477–485.

Shaham, Y. (1996). Effect of stress on opioid-seeking behavior:Evidence from studies with rats. Annals of Behavioral Medi-cine, 18, 255–263.


Shaham, Y., Adamson, L. K., Grocki, S., & Corrigall, W. A.(1997). Reinstatement and spontaneous recovery of nicotineseeking in rats. Psychopharmacology, 130, 396–403.

Shaham, Y., & Stewart, J. (1994). Exposure to mild stress en-hances the reinforcing efficacy of intravenous heroin self-ad-ministration in rats. Psychopharmacology, 114, 523–527.

Shaham, Y., & Stewart, J. (1995). Stress reinstates heroin-seekingin drug-free animals: An effect mimicking heroin, not with-drawal. Psychopharmacology, 119, 334–341.

Shaham, Y., & Stewart, J. (1996). Effects of opioid and dopaminereceptor antagonists on relapse induced by stress and re-expo-sure to heroin in rats. Psychopharmacology, 125, 385–391.

Shalev, U., Highfield, D., Yap, J., & Shaham, Y. (2000). Stress andrelapse to drug seeking in rats: Studies on the generality of theeffect. Psychopharmacology, 150, 337–346.

Shalev, U., Marinelli, M., Baumann, M., Piazza, P. V., & Shaham,Y. (2003). The role of corticosterone in food deprivation-in-duced reinstatement of cocaine seeking in the rat. Psychophar-macology, 168, 170–176.

Shalter, M. D. (1984). Predator–prey behavior and habituation. InH. V. S. Peeke & L. Petriovich (Eds.), Habituation, sensitiza-tion, and behavior (pp. 349–391). New York: Academic Press.

Shelton, K. L., Macenski, M. J., & Meisch, R. A. (1998). Rein-forcing effects of a combination of ethanol and methadonerelative to each drug alone. Pharmacology, Biochemistry, andBehavior, 61, 367–374.

Shuster, L., Webster, G. W., & Yu, G. (1975). Increased runningresponse to morphine in morphine-pretreated mice. Journal ofPharmacology and Experimental Therapeutics, 192, 64–67.

Shuster, L., Yu, G., & Bates, A. (1977). Sensitization to cocainestimulation in mice. Psychopharmacology, 52, 185–190.

Siegel, S. (1975). Evidence from rats that morphine tolerance is alearned response. Journal of Comparative and PhysiologicalPsychology, 89, 498–506.

Siegel, S. (1976, July 23). Morphine analgesic tolerance: Its situ-ation specificity supports a Pavlovian conditioning model. Sci-ence, 193, 323–325.

Siegel, S. (1977). Morphine tolerance acquisition as an associativeprocess. Journal of Experimental Psychology: Animal BehaviorProcesses, 3, 1–13.

Siegel, S. (1978). Tolerance to the hyperthermic effect of mor-phine in the rat is a learned response. Journal of Comparativeand Physiological Psychology, 92, 1137–1149.

Siegel, S., & Larson, S. J. (1996). Disruption of tolerance to theataxic effect of ethanol by an extraneous stimulus. Pharmacol-ogy, Biochemistry, and Behavior, 55, 125–130.

Siegel, S., & Sdao-Jarvie, K. (1986). Attenuation of ethanol tol-erance by a novel stimulus. Psychopharmacology, 88, 258–261.

Sinclair, J. D., & Li, T.-K. (1989). Long and short alcohol depri-vation: Effects on AA and P alcohol-preferring rats. Alcohol, 6,505–509.

Sinclair, J. D., & Senter, R. J. (1968). Development of an alcohol-deprivation effect in rats. Quarterly Journal of Studies on Al-cohol, 29, 863–867.

Sinha, R. (2001). How does stress increase risk of drug abuse andrelapse? Psychopharmacology, 158, 343–359.

Skinner, B. F. (1938). The behavior of organisms: An experimentalanalysis. New York: Appleton-Century-Crofts.

Slikker, W., Brocco, M. J., & Killam, K. F. (1984). Reinstatementof responding maintained by cocaine or thiamylal. Journal ofPharmacology and Experimental Therapeutics, 228, 43–52.

Sokolov, E. N. (1963). Perception and the conditioned reflex. NewYork: Macmillan.

Spanagel, R., & Holter, S. M. (1999). Long-term alcohol self-administration with repeated alcohol deprivation phases: Ananimal model of alcoholism? Alcohol & Alcoholism, 34, 231–243.

Spanagel, R., & Holter, S. M. (2000). Pharmacological validationof a new animal model of alcoholism. Journal of Neural Trans-mission, 107, 669–680.

Specker, S. M., Lac, S. T., & Carroll, M. E. (1994). Food depri-vation history and cocaine self-administration: An animal modelof binge eating. Pharmacology, Biochemistry, and Behavior, 48,1025–1029.

Staddon, J. E. R., & Higa, J. J. (1996). Multiple time scales insimple habituation. Psychological Review, 103, 720–733.

Stewart, J., & de Wit, H. (1987). Reinstatement of drug-takingbehavior as a method of assessing incentive motivational prop-erties of drugs. In M. A. Bozarth (Ed.), Methods of assessing thereinforcing properties of abused drugs (pp. 211–227). NewYork: Springer-Verlag.

Stewart, J., de Wit, H., & Eikelboom, R. (1984). Role of uncon-ditioned and conditioned drug effects in the self-administrationof opiates and stimulants. Psychological Review, 91, 251–268.

Stewart, J., & Wise, R. A. (1992). Reinstatement of heroin self-administration habits: Morphine prompts and naltrexone dis-courages renewed responding after extinction. Psychopharma-cology, 108, 79–84.

Stretch, R., & Gerber, G. J. (1973). Drug-induced reinstatement ofamphetamine self-administration behaviour in monkeys. Cana-dian Journal of Psychology, 27, 168–177.

Strubbe, J. H., & van Dijk, G. (2002). The temporal organizationof ingestive behaviour and its interaction with regulation ofenergy balance. Neuroscience and Biobehavioral Reviews, 26,485–498.

Swithers, S. E., & Hall, W. G. (1994). Does oral experienceterminate ingestion? Appetite, 23, 113–138.

Thompson, R. F., & Spencer, W. A. (1966). Habituation: A modelphenomenon for the study of neuronal substrates of behavior.Psychological Review, 73, 16–43.

Thorpe, W. H. (1966). Learning and instinct in animals. Cam-bridge, MA: Harvard University Press.

Tiffany, S. T. (1990). A cognitive model of drug urges anddrug-use behavior: Role of automatic and nonautomatic pro-cesses. Psychological Review, 97, 147–168.

Vanderschuren, L. J. M. J., & Kalivas, P. W. (2000). Alterations indopaminergic and glutamatergic transmission in the inductionand expression of behavioral sensitization: A critical review ofpreclinical studies. Psychopharmacology, 151, 99–120.

Vanderschuren, L. J. M. J., Schoffelmeer, A. N. M., Mulder, A. H.,& De Vries, T. J. (1999a). Dopaminergic mechanisms mediatingthe long-term expression of locomotor sensitization followingpreexposure to morphine or amphetamine. Psychopharmacol-ogy, 143, 244–253.

Vanderschuren, L. J. M. J., Schoffelmeer, A. N. M., Mulder, A. H.,& De Vries, T. J. (1999b). Lack of cross-sensitization of thelocomotor effects of morphine in amphetamine-treated rats.Neuropsychopharmacology, 21, 550–559.

Wagner, A. R. (1976). Priming in STM: An information-process-ing mechanism for self-generated or retrieval-generated depres-sion in performance. In T. J. Tighe & R. N. Leaton (Eds.),Habituation: Perspectives from child development, animal be-havior, and neurophysiology (pp. 95–128). New York: Wiley.

Walter, T. A., & Riccio, D. C. (1983). Overshadowing effects inthe stimulus control of morphine analgesic tolerance. Behav-ioral Neuroscience, 97, 658–662.


Wang, N. S., Brown, V. L., Grabowski, J., & Meisch, R. A. (2001).Reinforcement by orally delivered methadone, cocaine, andmethadone–cocaine combinations in rhesus monkeys: Are thecombinations better reinforcers? Psychopharmacology, 156,63–72.

Weeks, J. R. (1962, October 12). Experimental morphine addic-tion: Method for automatic intravenous injections in unre-strained rats. Science, 138, 143–144.

Weiss, F., Hurd, Y. L., Ungerstedt, U., Markou, A., Plotsky, P. M.,& Koob, G. F. (1992). Neurochemical correlates of cocaine andethanol self-administration. Annals of the New York Academy ofSciences, 654, 220–241.

Wenger, J. R., Tiffany, T. M., Bombardier, C., Nicholls, K., &Woods, S. C. (1981, July 31). Ethanol tolerance in the rat islearned. Science, 213, 575–577.

Whitlow, J. W., Jr. (1975). Short-term memory in habituation anddishabituation. Journal of Experimental Psychology: AnimalBehavior Processes, 1, 189–206.

Wikler, A. (1948). Recent progress in research on the neurophys-iological basis of morphine addiction. American Journal ofPsychiatry, 105, 329–338.

Wise, R. A. (1982). Common neural basis for brain stimulationreward, drug reward, and food reward. In B. G. Hoebel & D.Novin (Eds.), Neural basis of feeding and reward (pp. 445–454). Brunswick, ME: Haer Institute.

Wise, R. A., & Bozarth, M. A. (1987). A psychomotor stimulanttheory of addiction. Psychological Review, 94, 469–492.

Wise, R. A., Leone, P., Rivest, R., & Leeb, K. (1995). Elevationsof nucleus accumbens dopamine and DOPAC levels duringintravenous heroin self-administration. Synapse, 21, 140–148.

Wisniewski, L., Epstein, L. H., & Caggiula, A. R. (1992). Effect offood change on consumption, hedonics, and salivation. Physi-ology & Behavior, 52, 21–26.

Woolverton, W. L., Cervo, L., & Johanson, C. E. (1984). Effectsof repeated methamphetamine administration on methamphet-amine self-administration in rhesus monkeys. Pharmacology,Biochemistry, and Behavior, 21, 737–741.

Received September 16, 2003Revision received March 10, 2004

Accepted September 7, 2004 �


Regulation of Drug Taking by Sensitization and Habituation.

Documents

Transcript of Regulation of Drug Taking by Sensitization and Habituation.