Baker & Tiffany (1985).pdf

Psychological Review Copyright 1985 by the American Psychological Association, Inc. 1985, Vol. 92, No. 1, 78-108 0033,295X/85/$00.75

Morphine Tolerance as Habituation

T imothy B. Baker and Stephen T. Tiffany University of Wisconsin--Madison

We propose that the development of drug tolerance is congruent with the behavioral characteristics of habituation. Specifically, we show that morphine tolerance development conforms to Wagner's priming model of habituation. Tolerance develops through both associational and nonassociational routes; We attribute associational tolerance development to retrieval-generated priming of memory, whereas nonassociational tolerance we attribute to self-generating priming. This model accounts for the effects of the following on tolerance development: dose level, drug signaling, and interdose interval. Also, an habituation model is consistent with data showing that dose level and interdose interval affect the impact of drug signals on tolerance development.

In general terms, drug tolerance refers to a decreased effect of a drug dose with repeated administration. Thus, in the tolerant animal, a larger dose of drug must be administered in order to reinstate an initial drug effect. A more precise definition of the phenomenon is that tolerance represents a shift in the dose response curve to the right (Fernandes, Kluwe, & Coper, 1977; Kalant, LeBlanc, & Gibbins, 1971). Iterative administration of certain drugs can produce remarkable amounts of tolerance. In humans, for example, an initial dose of 100-200 mg of morphine produces profound sedation, severe respiratory depression, and death (Jaffe & Martin, 1980), whereas tolerant subjects can be administered as much as 4 g without adverse effect (Wil- liams & Oberst, 1946). Extraordinary levels of opiate tolerance can also be produced in animals. For instance, Mucha, Kalant, and Linseman (1979) demonstrated that 975 mg! kg of morphine elicited only a slight analgesia in rats that had been exposed to a high dose of morphine for 24 consecutive days. Mor-

This project was supported, in part, by National Institutes of Drug Abuse Award I-RO1-DA02729-02 and Wisconsin Alumnus Research Foundation Award 135- 3045. S. Tiffany is now at Purdue University.

The authors thank Dale S. Cannon, June Dahl, Eileen Martin, Sue Mineka, Joseph Newman, and Diane Zelman for their helpful suggestions. We also thank Ray Kesner who provided us with a great deal of assistance and guidance in our discussions of morphine tolerance.

Requests for reprints should be sent to Timothy B. Baker, Department of Psychology, University of Wisconsin, Madison, Wisconsin 53706.

phine-naive animals were extremely analgesic following an injection of 63 mg/kg.

Tolerance is clinically important because it explains a central feature of addiction; that is, addicts require and self-administer in- creasing amounts of drug in order to obtain desired effects. In addition, tolerance is important to researchers interested in drug dependence. Drugs that produce physical dependence also produce tolerance, and there is a rough temporal correlation between the development of these two phenomena (although cf. Majchrowicz & Hunt, 1976; Ritz- mann & Tabakoff, 1976b). This suggests that drug tolerance and dependence may be subserved by the same, or similar, mechanisms. Indeed, many current behavioral and physiological theories of drug addiction contain the notion that the same processes that produce tolerance also produce signs and symptoms of withdrawal once drug is cleared from the body (Goldstein & Goldstein, 1968; Hin- son & Siegel, 1980; Kosterlitz & Hughes, 1975; Solomon, 1977).

Until recently, the study of drug tolerance was considered the exclusive domain of phar- macologists and neurobiologists. In theories promulgated by these researchers the adaptive responses to drug that produce tolerance depended only on drug exposure parameters such as dose, duration of drug administration, and frequency of dosings. Thus, according to these theories drug exposure activates processes such as immunological reactions (Cochin, 1972), derepressant mechanisms (Shuster, 1971), or receptor supersensitivity

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TOLERANCE AS HABITUATION 79

(Collier, 1968), and these account for decreased drug effects.

Beginning in the late 1960s studies began to appear that indicated that environmental manipulations exerted potent effects on tolerance development, effects that were neither predicted nor easily explained by traditional pharmacological models. Mitchell and his colleagues (Adams, Yeh, Woods, & Mitchell, 1969; Ferguson, Adams, & Mitchell, 1969; Kayan, Woods, & Mitchell, 1969) showed that maximal levels of tolerance are obtained only when tolerance development and testing are conducted in the same environment. For instance, Adams et al. (1969) found that rats exhibited enhanced tolerance to morphine's analgesic effects only when tolerance development and tolerance testing occurred in the same environment (a hot-plate testing apparatus). Moreover, this facilitation of tolerance did not depend on practice making the analgesic test response (a paw-lick); rats showed enhanced tolerance even if the hot plate were at ambient temperature during tolerance development (which obviated nociceptive response). The authors also found that hot- plate exposure produced enhanced tolerance only when exposure was temporally contiguous with drug delivery. Adams et al. (1969) were unable to explain their findings, but suggested that they might depend on the co- occurrence of drug effects and stress (produced by test-environment exposure).

In the mid 1970s Siegel initiated a remarkable series of experiments that suggested that the contextual enhancement of tolerance found by Mitchell and his colleagues was due to Pavlovian conditioning (e.g., Siegel, 1975; Siegel, 1977). Siegel (1975) reported that the enhanced tolerance acquired through previous drug-environment pairings can be extin- guished by exposing animals to the test environment without drugs. Siegel (1977) also found that latent inhibition and partial reinforcement manipulations affect tolerance development. Thus, exposure to tolerance test cues prior to morphine delivery retards tolerance development; likewise, degrading the contingency between morphine delivery and test-environment exposure slows the rate of tolerance acquisition.

Shortly after Siegel published his theory that Pavlovian conditioning accounts for some

instances of tolerance development, it was suggested that environmental enhancement of tolerance is merely an artifact produced by stress or novelty (Bardo & Hughes, 1979; Carder, 1978; Sherman, 1979). However, research has shown that this is not the case (e.g., Gebhart, Sherman, & Mitchell, 1972; Kesner & Baker, 1981; Siegel, 1977). Test- environment novelty or stress can affect measures of tolerance development (e.g., nociceptive and pyretic response; Tiffany & Baker, 1981; Tiffany, Petrie, Baker, & Dahl, 1983; Zelman, Tiffany, & Baker, 1985), but cannot provide an adequate account of the reliable enhancement of tolerance development due to the presence of contingent drug signals.

Considerable evidence now indicates that environmental manipulations can influence tolerance development per se. Moreover, the substantial congruence between the Pavlovian learning paradigm and the enhancement of tolerance development by drug contingent cues suggest that tolerance development may conform to a traditional model of behavior change (e.g., Pavlovian learning, habituation). In this article we present an habituation model of tolerance that provides a more complete, accurate, and parsimonious account of morphine tolerance development than do other behavioral models. In particular, we compare our habituation model of tolerance with Siegel's Pavlovian tolerance model and with Solomon's opponent-process model.

We restricted our analysis of tolerance by concentrating on research done with morphine because (a) the morphine tolerance literature is the only drug literature extensive enough to permit firm conclusions regarding the behavioral characteristics of tolerance, (b) the tolerance theories that we will evaluate have been used to explain morphine tolerance phenomena, and (c) characteristics of morphine (e.g., reliability and magnitude of tolerance development, naloxone reversibility of agonistic effects) yield a body of research that permits definitive conclusions concerning the development of tolerance. Our analysis focuses on the antinociceptive, pyretic, and activating effects of morphine in the rat, as these responses have been the most frequently studied in the morphine tolerance literature. We believe that an accurate portrayal of tolerance

80 TIMOTHY B. BAKER AND STEPHEN T. TIFFANY

development occurs only through a detailed examination of specific tolerance phenomena.

Siegel's Pavlovian Model

Two Pavlovian models of tolerance exist: Siegel's Pavlovian model and Wikler's successive-adaptations model. However, we present and discuss only Siegel's model because it is more closely tied to a supporting data base. Furthermore, Wikler's (e.g., Wikler, 1973) model contains physiological theorizing that makes straightforward interpretation and prediction difficult. Because the basic features of Siegel's model have been described numerous times (e.g., Kesner & Baker, 1981; Hinson & Siegel, 1980), we will only briefly review its principal features.

In Siegers Pavlovian tolerance model a drug serves as an unconditioned stimulus (UCS) that produces direct or unconditioned effects (UCRs). In the case of morphine, UCRs would be agonistic effects like analgesia, pyretic changes, and respiratory depression. Siegel posited that cues routinely paired with drug administration come to elicit conditioned responses (CRs) that are opposite in direction to the UCRs produced by the drug (Siegel, 1975). Siegel refered to these drug antagonistic CRs as compensatory responses. With morphine-induced analgesia, the CR would be a compensatory response of hyperalgesia (Krank, Hinson, & Siegel, 198 l; Siegel, 1975). Likewise, if an animal's UCR to a morphine dose is hyperthermia, the animal's compensatory response should be hypothermia. It is assumed that such CRs increase in size with repeated drug exposure and thereby reduce unconditioned drug effects; this reduction constitutes tolerance. Siegers model is silent with respect to tolerance acquired independent of drug-environment contingencies.

Opponent-Process Model

Solomon's opponent-process model (So- lomon, 1977, 1980; Solomon & Corbit, 1974) is predicted on the notion that the central nervous systems of mammals are organized to oppose diverse types of affectual or hedonic states. Opponent processes are mobilized by events or stimuli that serve as effective Pav- lovian UCSs and operant reinforcers. An

effective UCS produces a primary hedonic process that is determined by UCS intensity, quality, and duration. Primary hedonic processes may be thought of as the direct effects of the UCS on the organism. Such a-processes are phasic and show little habituation. These a-processes automatically elicit a secondary b-process that opposes or suppresses the hedonic state generated by the onset of the a- process. In contrast to the a-process, the b- process (a) has a longer latency to onset, (b) increments gradually over UCS administration trials, and (c) is slow to decay and, therefore, persists well after the cessation of the eliciting UCS and the a-process. According to this theory, the affective or hedonic status of an organism is approximated by the sum of the opposing a- and b-processes. Thus, this model is homeostatic in that "opp0nent-processes defend a hedonic equilibrium" (Solo- mon & Corbit, 1974, p. 143).

According to the opponent-process theory, drug doses engender a-processes because they serve as effective UCSs and operant reinforcers (e.g., Cannon, Berman, Baker, & Atkinson, 1975; Miksic, Smith, Numan, & Lal, 1975; Schuster, Dockens, & Woods, 1966; White, Sklar, & Amit, 1977). Drug a-processes would consist of direct effects that are associated with intoxication. In the case of morphine, these processes would be evidenced by effects such as analgesia, respiratory depression, and hypothermia (at high doses). It is well-known that these opiate effects decrease with repeated morphine exposures. This occurs, according to the opponent-process theory, because every time a-processes are elicited, b-processes are recruited. With successive recruitment, the secondary processes are strengthened and, therefore, become increasingly effective in reducing the initial effects of drug. Hence, b- processes subserve phenomena that are traditionally labeled as tolerance. There are some restrictions on this growth of b-processes, however; for example, widely separated drug exposures do not result in much accretion of b-processes. In addition, the magnitude of b- processes is positively related to the magnitude of the initial a-process induced by drug. Last, once strong and powerful b-process recruitment is achieved, there are "savings" that permit its rapid rerecruitment after long intervals.


Solomon's (1977) model is relevant to both tolerance and dependence. It is assumed that as b-processes build in strength, they over- whelm drug agonistic effects producing both tolerance and signs of partial withdrawal. Of course, withdrawal is maximal when drug is cleared from the body and the b-process is unopposed by the a-process. Unlike Siegel's Pavlovian model, the opponent-process model is not strictly associational, as tolerance is produced by homeostatic reactions to drug effects that may or may not be associated with drug-contingent cues. Moreover, according to the opponent-process model both direct drug effects (a-processes) and homeostatic responses (b-processes) may be associated with drug signals. Siegel (1981) assumed that any drug CR elicited in a tolerant organism must be opposite in direction to initial drug effects (if the animal is indeed tolerant to that effect). Solomon, on the other hand, posited that neutral stimuli can become associated with either a- or b-processes: Stimuli associated with a-processes yield drug- isodirectional CRs that are followed by drug-antagonistic responses, whereas stimuli associated with b-processes elicit only drug- antagonistic CRs. The crucial factors that determine whether environmental stimuli are associated with a- or b-processes are unspec- ified. However, Solomon (1977) speculated that the temporal relationship between the CS and the elicitation of a- and b-processes may be prepotent.

Habituation Model

The habituation model, similar to the two- process model of tolerance originally proposed by Kesner and Baker (1981; also see Siegel's, 1977, earlier discussion of the relevance of habituation theory to tolerance development), is based on the assumption that behavioral aspects of tolerance are best conceptualized as reflecting characteristics of habituation that have been elucidated in other sorts of behavioral and neurophysiological research. We are presenting this new model because other behavioral models of tolerance do not account for recent findings from morphine tolerance research. Our habituation model yields more accurate predictions than the Pavlovian or opponent-process models re-

garding the effects of variables such as interdose interval, drug signals, and drug dose on tolerance development. Moreover, we contend that morphine tolerance is not subserved by drug-antagonistic responses observable at the behavioral level. Obviously, animals undergo physiological changes during tolerance development, rendering them less sensitive to drug. However, we do not believe that tolerance is subserved by homeostaticlike responses that follow initial drug effects (cf. opponent-process theory) or that are elicited by cues previously paired with drug (cf. Siegel's Pav- lovian tolerance model). Drug-antagonistic CRs may be observed in some circumstances (Eikelboom & Stewart, 1982), but according to our theory these are not essential for tolerance development.

Tolerance refers specifically to the occurrence of decreased response to drug. This fits quite well with a general definition of habituation, that is, decreased responding to repeated stimulation (Groves & Thompson, 1970). Although numerous models of habituation exist (e.g., Groves & Thompson, 1970; Konorski, 1967; Sokolov, 1963; Thompson & Spencer, 1966; Wagner, 1976, 1978, 1979), and although they differ with respect to iso- lated habituation phenomena (e.g., the incre- mental intensity effect; Groves & Thompson, 1970) and postulated mechanisms, they are in close agreement regarding the general characteristics of habituation. Therefore, many features of our tolerance model are consistent with characteristics of habituation as depicted in a number of habituation theories. We do make extensive use of Wagner's concepts of associatively- and self-generated priming to explain the impact of environmental contingencies on tolerance development. Although other theorists have suggested that habituation is influenced by associational processes (e.g., Stein, 1966), Wagner's theory offers the most explicit model regarding the operation of associative mechanisms within an habituation framework. Associational habituation processes are important to our tolerance model inasmuch as numerous findings show that tolerance develops through both associational and nonassociational routes. The terms associational and nonassociational refer to tolerance that can and cannot, respectively, be attributed to drug-environment contin-


gencies. We believe that the general characteristics of habituation are remarkably consistent with a wide variety of tolerance phenomena. Furthermore, we find a striking correspondence between predictions derived from Wagner's model of habituation and the impact of contextual manipulations on tolerance development.

Although Wagner and his associates have provided compelling evidence that his general model has wide applicability to a number of basic conditioning phenomena (e.g., Terry & Wagner, 1975; Wagner, 1976, 1978, 1979, 1981), the findings of greatest relevance to our account of tolerance arise from research investigating the roles of self- and associatively-generated priming in habituation (Davis, 1970; Donegan, 1981; Terry, 1976; Whitlow, 1975). According to Wagner's habituation model, a stimulus presentation is more or less surprising to the extent that it is already represented or primed in short- term memory (STM). A surprising event is more likely than an expected event to initiate stimulus processing. Amount and duration of such processing determines the magnitude of unconditioned responding to the stimulus. An expected event (i.e., one already primed in STM) elicits less stimulus processing and, consequently, evokes a diminished response to the stimulus event. This decreased responding constitutes habituation. Wagner (1976, 1978) forwarded two mechanisms to account for the reduction in stimulus processing, and subsequent suppression of unconditioned responding, when stimuli are primed in memory. In one formulation he borrowed from information-processing theory (e.g., Atkinson & Shiffrin, 1968) and argued that the suppressive effects of priming arise as a natural consequence of the operating characteristics of STM, In another formulation, Wagner (1979) presented an extension of Konorski's (1967) model of habituation in which priming activates an "inhibitory per- ceptive recurrent reflex" that functions to suppress stimulus input as well as various indices of stimulus processing. It is important to note that Wagner's model is not dependent on the involvement of STM. Both formula- tions of his model yield similar predictions with respect to tolerance development. How- ever, we use Wagner's memory model of

habituation for the purposes of explication because we believe that memory, or memo- rylike processes, are crucial to the development of tolerance to the central nervous system (CNS) effects of drugs.

According to Wagner's model, there are two principal ways that a stimulus may be primed in memory. Associatively generated priming refers to the case where a stimulus representation is introduced into STM through the presentation of a second stimulus that had previously been paired with the target stimulus ((~hman, 1979; Wagner, 1979). For example, if a light flash and a distinctive context had been repeatedly paired, then reexposure to the context would prime the light representation in STM. Presentation of the light flash when it was already primed in memory would render the stimulus less surprising and thus reduce processing. The net effect would be a reduction in unconditioned responding to the light. As Wagner (1976) noted, this resembles the conditioned dimi- nution of the UCR effect, in which magnitude of a UCR is diminished through its pairing with a predictive CS (cf. Donegan, 1981; Kimmel, 1966). In self-generated priming, the stimulus representation becomes primed in memory, not through the associative action of stimulus-paired cues but rather, through the prior recent presentation of the stimulus itself. Thus, if a stimulus is presented while its representation is still primed in memory due to a previous presentation, it evokes less processing and hence a corresponding reduction in unconditioned responding. Priming, whether it is self-generated or associatively generated, produces a decrement in unconditioned responding, that is, priming results in habituation.

Opiate tolerance can be viewed as concor- dant with predictions derived from Wagner's model if the following assumptions are made. First, exposure-to-drug produces a representation of the drug stimulus in memory (self- generated priming); the magnitude and duration of the priming is directly related to the drug dose. Thus, the influence of self- generated priming on habituation is of greater magnitude and duration as a positive function of dose. Second, presentation of a cue previously paired with drug results in associatively generated priming of memory with a me-


morial representation of the drug's stimulus properties. Third, both self-generated and associatively generated priming result in decreased neural processing of the drug stimulus. Such decreased processing of drug stimulus information results in attenuated behavioral effect and constitutes tolerance. The extent and duration of elicitation of tolerance mechanisms is a direct function of the magnitude and duration of the priming. Finally, the degree of tolerance observed on any given occasion is directly related to the extent to which a representation of the drug's stimulus properties was primed at the time of drug delivery.

The particular mnestic approach to habituation advocated in this article is intended to provide a vehicle for the integration of both associational and nonassociational aspects of tolerance development into a coherent model. Such an approach is justified in light of evidence that, in the intact animal, there are interactions between associative and nonassociative tolerance processes that affect both the magnitude and retention of tolerance. The major reason for adopting a memory model of tolerance is simply that it provides the most accurate and compelling predictions of the characteristics of tolerance development. We recognize that all tolerance phenomena cannot be attributed to the priming of memory (see our discussion of tolerance in vitro). However, we contend that in the intact organism, tolerance processes operate in a manner consistent with traditional char- acterizations of memory constructs.

As noted earlier, in one formulation of his model Wagner uses the STM construct (At- kinson & Shiffrin, 1968) to account for some important characteristics of habituation. For instance, if stimulus presentations are widely spaced in time, habituation is retarded or reduced. Ostensibly this arises as a consequence of the brief retentive properties of STM. We propose a similar relationship between interdose interval and tolerance development; tolerance development is reduced as the interdose interval increases. However, we do not invoke a STM memory construct in our tolerance model because the temporal parameters of tolerance development, and those of habituation to exteroceptive stimuli, are so divergent. Although the retentive ca-

pacity of STM is traditionally measured in seconds, drug effects may last many hours.

We propose that there is a memory register that retains information about a drug's stimulus properties for many hours after drug administration. This register has properties that are similar to those of STM. For example, both the hypothetical memory register and STM (with particular reference to Wagner's use of the construct) spontaneously decay over time; both result in decreased behavioral response as an inverse function of interstimulus interval, and duration of rehearsal in both is a positive function of stimulus intensity (or drug dose). The only distinction we make between these two constructs is that the temporal parameters of the memory register are greatly elongated. This, we suggest, results in tolerance and habituation adhering to the same principles of development and retention, despite having very different temporal parameters. Thus, tolerance and habituation share a relationship similar to that shared by taste-aversion learning and Pavlov- ian conditioning (Domjan, 1980; Spiker, 1977). The principles of taste-aversion conditioning appear to be virtually identical to principles of Pavlovian conditioning with exteroceptive stimuli, yet the temporal parameters of each are widely divergent (Logue, 1979).

A central tenet of our model is that drugs have salient stimulus properties and that these may be retained in memory for long periods of time. There is ample evidence to support this notion. Not only do drugs exert effects that last many hours (e.g., Rosow, Miller, Pelikan, & Cochin, 1980), but animals re- spond to the discriminative stimulus properties of drugs in operant tasks for many hours after drug administration (Barry & Krimmer, 1978a; Colpaert & Rosecrans, 1978). For instance, the discriminative stimulus properties of amphetamine have been shown to persist for as long as 8 hours after drug delivery (Huang & Ho, 1974). We propose that a drug's stimulus properties are retained via rehearsal in a memory register even atter the drug loses its discriminative stimulus properties.

Across iterative dotings, many drug effects decrease as animals become tolerant. This seems anomalous for an habituation model


of tolerance because this theory suggests that drugs have distinct stimulus properties that remain relatively invariant across repeated administrations. There is considerable evidence that suggests that drugs do have characteristic stimulus properties that animals consistently detect even after tremendous amounts of drug exposure (Barry & Krimmer, 1978b; Jarbe & Holmgren, 1977; York & Winter, 1975). Based on research with morphine and other opioid drugs, Colpaert (1978) concluded that there is no good evidence that animals ever become insensitive to certain stimulus properties of opiates. Thus, both in habituation to exteroceptive stimuli and tolerance development to drugs, stimulus rec- ognition can be maintained across iterative stimulus presentation, whereas responding declines.

At present it is not known what stimulus properties of drugs are crucial to tolerance display. Drug stimulus properties that serve as discriminative stimuli in operant tasks are not necessarily the same as those that are primed and result in tolerance (cf. Kallman & Rosecrans, 1978). It is likely that stimulus properties that are primed are mediated via the afferent arm of the CNS (Eikelboom & Stewart, 1982). In addition, the behavioral and physiological effects of drugs to which animals become tolerant are not themselves primed, drug stimulus properties. Primed stimulus properties are necessarily interocep- tive, afferently mediated signals relaying information on initial drug actions on afferent or efferent arms of the CNS.

Our habituation model yields the following predictions regarding morphine tolerance development: In the absence of reliable drug signals, tolerance development varies as an inverse function of interdose interval (IDI). This is a straightforward generalization from habituation research where response decrement over iterative stimulation is inversely related to interstimulus interval (cf. Davis, 1970; Graham, 1973; Groves & Thompson, 1970; Prokasy, 1965; Thompson & Spencer, 1966). Wagner's notions of self-generated priming are also perfectly congruent with this prediction as the degree of self-generated priming encountered on any given drug administration trial should decrease as IDI is increased.

The habituation literature suggests that the relationship between stimulus intensity and magnitude of habituation is complex (Gra- ham, 1973; Groves & Thompson, 1970). The nature of this relationship is dependent on the measures one uses to define habituation (e.g., relative vs. absolute habituation; Groves & Thompson, 1970). If magnitude of habituation is assessed by determining the shift to the right of the intensity-response curve in habituated animals (this is comparable to defining tolerance as a shift in the dose- response curve to the right), then habituation may be seen to vary as a positive function of stimulus intensity (Graham, 1973). Similarly, we expect nonassociational tolerance development to increase as a positive function of dose. This prediction is an empirical generalization from habituation research and is also consistent with our assumption that the duration and magnitude of self-generated priming induced by any given drug exposure is a direct function of the drug dose. It is well-known that duration of drug effects and persistence of drug in the body are positively related to dose (Levine, 1978). As stated earlier, if an organism is exposed to drug while memory is already primed due to a previous drug administration, then the organism will exhibit drug tolerance. Thus, nonassociational tolerance should vary directly with dose and inversely with IDI.

In general, when drugs are administered in the presence of a reliable drug signal or contingent context (Estes, 1973), tolerance will be acquired and will be manifest to the extent that tolerance is assessed in the presence of those cues. According to our tolerance model, presentation of a stimulus previously paired with drug evokes associatively generated priming. Consequently, an animal exposed to the drug with the drug already represented in a memory register will exhibit drug tolerance, as the priming elicits drug tolerance mechanisms. Associational tolerance shows different temporal patterns of acquisition and retention than does nonassociational tolerance, largely because the former is not constrained by the persistence of tolerance processes per se (i.e., the natural decay function of the memory register). Thus, the presence of drug signals should allow tolerance development at lower doses and longer IDIs


than is the case with unsignaled drug delivery. This is because with associational tolerance, tolerance development does not depend on prolonged maintenance of a drug's stimulus properties in the memory register, which requires high doses and brief IDIs. Rather, the drug signal or context primes a representation of the drug in memory, prior to each subsequent drug dose. An understanding of self- generated and associatively generated priming also yields the straightforward prediction that tolerance should be retained longer if tolerance development and retention involve signaled, as opposed to unsignaled, drug delivery. Con- sequently, spontaneous recovery is more likely with unsignaled drug delivery than with signaled drug administration.

The habituation model suggests that animals tolerant to one drug should show gen- eralized habituation (cross tolerance) to drugs with similar stimulus properties. In addition, cross tolerance should also be observed between opiate tolerance and stress responses that are mediated by endogenous opiate systems. Generalization of habituation is, of course, compatible with a number of habituation models (e.g., Konorski, 1967; Sokolov, 1963; Wagner, 1976). According to our tolerance model, priming elicits tolerance mechanisms that are effective in reducing particular effects of pharmacologically related drugs. Characteristics such as retention and contextual specificity differ for various instances of cross tolerance depending on whether the original tolerance was subserved by self-generated or associatively generated priming.

Last, if an animal acquires tolerance with reliable drug-cue contingencies, it shows a loss of tolerance if drug is later presented temporally concommitant with a novel, salient stimulus. That is, animals show dishabituation (Sokolov, 1963; Thompson & Spen- cer, 1966). There are numerous examples of dishabituation in the habituation literature. Hammond (1967), for example, found that blasts of an automobile horn resulted in increased electrodermal responses to previously habituated light and tone stimuli. Dis- habituation can be explained by Wagner's habituation theory (e.g., Whitlow, 1975). A novel, salient stimulus presented in the context of signaled drug delivery should interfere with maintenance of the drug's stimulus

properties in the memory register or with their retrieval from long-term store. Disha- bituation of nonassociational, compared to associational, tolerance may be less robust because the memory priming induced by recent, prior drug exposure would probably not be as vulnerable to the disruptive effects of novel stimulation as the process of associatively generated priming.

One characteristic of our model is not directly derived from the behavioral literature on habituation: Dose and IDI interact with the efficacy of drug signals. When drug is delivered with salient cues, animals develop tolerance at dose levels too low or IDIs too long to produce tolerance with unsignaled drug administration. However, if drug dose is substantially increased, animals become tolerant whether or not drug delivery is signaled. At sufficiently high dose levels, delivered at sufficiently short IDIs, tolerance development is so substantial that the presence of drug signals exerts relatively little effect. Thus, the relative impact of drug-cue contingencies decreases as a negative function of dose and a positive function of IDI. The predicted interaction of dose and IDI with associational tolerance acquisition is consistent with Wagner's (1978) contention that self-generated priming disrupts the acquisition of a conditioned response when the priming US and training US are the same. For instance, Terry (1976) demonstrated that a US presented just prior to a CS-US trial produced a decrement in conditioning. The dec- remental influence of US priming on conditioning was found to be stimulus specific (i.e., the decrement was greatest when the priming and conditioning US were the same), was reduced by the interpolation of a novel stimulus between the priming US and the subsequent CS-US presentations, and occurred even when the priming US was embedded within the CS-US trial. Terry interpreted these data as supportive of Wag- ner's (1976) hypothesis that self-generated priming of a US in STM can reduce the effectiveness of the US in instigating processing steps necessary for associative learning.

Self-generated priming should have a similar effect on the acquisition of associative tolerance. That is, self-generated priming should diminish the association of a salient


cue with a drug representation (i.e., reduce the acquisition of associativcly generated processes) to the extent that the self-generated priming persists until the conditioning trial. Wagner (1978) would attribute this effect to a decrease in rehearsal of a stimulus in STM when a representation of that stimulus was already primed in STM. Thus, conditions conducive to the acquisition of nonassociational tolerance (high doses and/or short IDIs) would be detrimental to the development of associational tolerance. This same reasoning suggests that procedures favorable to the acquisition of associational tolerance (e.g., lower doses or longer IDIs) are incompatible with the development of nonassociational tolerance.

Many of the relationships we have described could be derived from the two-process tolerance model proposed by Kesner and Baker (1981). In this model, tolerance attributable to unsignaled drug delivery was viewed as an example of habituation; the Pavlovian paradigm (Siegel, 1977) was used to explain tolerance that developed as a function of signaled drug delivery. We have abandoned a Pavlovian model as an explanation of associational tolerance for a variety of reasons that are dis- cussed throughout this article. One reason is that, by definition, tolerance is more analo- gous to habituation than is Pavlovian learning; that is, it is a decrement in behavioral response to drug as a function of repeated stimulation. Also, all of the associational tolerance phenomena that Siegel has used to support his Pavlovian tolerance model (e.g., latent inhibition, extinction of tolerance, partial reinforcement effects) are just as easily accounted for by associatively generated priming mechanisms (Wagner, 1978). Finally, a Pavlovian tolerance model requires a dem- onstration, independent of reduced drug effect per se, of a learned response that is compensatory for an initial direct drug effect. Siegel (in 1983) has presented examples of what he considers to be specific compensatory responses that purportedly subserve tolerance by counteracting drug effects. However, we believe that recent data (e.g., Tiffany, Petrie, Baker, & Dahl, 1983) indicate that such compensatory responses are not necessary to the development of associational tolerance. Therefore, we sec no compelling evidence

that Pavlovian conditioning is relevant to morphine tolerance development.

All three tolerance models that we have presented are compatible with the proposition that both associational and nonassociational mechanisms may contribute to tolerance development. However, the habituation model is unique in that it makes precise statements about the development of both associational and nonassociational tolerance, and makes specific predictions about the interaction of these two types of tolerance. Siegel (1978) acknowledged that tolerance occurs in the absence of drug-cue contingencies, but his Pavlovian model does not account for nonassociational tolerance phenomena. Solomon's opponent-process model provides a general description of the gross features of drug tolerance and dependence, yet it does not suggest that drug-cue contingencies should affect the rate of tolerance development. Cer- tain features of the habituation model, designed to account for both associational and nonassociational tolerance, yield predictions that are not straightforward extensions of the other two models:

I. Tolerance can be acquired with or without reliable drug signals. However, rate or magnitude of acquisition are generally greater with reliable drug signals.

2. Tolerance is acquired with longer interdose intervals and at lower doses when drug delivery is signaled than when it is unsignaled.

3. The proportion of a tolerance phenomenon attributable to associational mechanisms is, in general, an inverse function of dose, and a positive function of IDI.

4. Tolerance is retained longer if animals are trained and tested in the presence of contingent drug signals than if they are not. In addition to these predictions, others center around the directionality of conditioned morphine effects vis-a-vis morphine's unconditioned or agonistic actions (i.e., actions directly produced by occupation of a drug's receptor site). For instance, both Siegel's Pav- lovian model and the opponent-process model are homeostatic adjustment models: Drugs exert initial, unconditioned actions (e.g., analgesia) that are countered by later homeostatic responses (e.g., hyperalgesia). In the Pavlovian model, over the course of tolerance development, drug signals are only associated


with homeostatic responses in response systems in which tolerance accrues. Thus, drug signals presented to tolerant animals should elicit reduced unconditioned or agonistic effects (tolerance) in drugged organisms, and drug compensatory responses (opposite to initial drug effects) in nondrugged animals. The opponent-process model differs from the Pavlovian model in that it predicts that drug- agonistic effects as well as subsequent opponent processes may be associated with drug signals. Thus, if a drug signal is repeatedly paired with a particular drug effect, to which animals have become tolerant, the cue may elicit the initial drug effect followed by a homeostatic response, or enhanced homeostatic response per se (the opponent process; i.e., tolerance), in drugged or undrugged tolerant organisms.

Opiates are generally considered to produce two general classes of actions, that is, activating (hyperactivity, hyperthermia) and depressant (inactivity, hypothermia) effects (Jacquet, Klee, Rice, Iijima, & Minamikawa, 1977; Labella, Pinsky, & Havlicek, 1979; Tatum, Seevers, & Collins, 1929; Villareal & Castro, 1979). Although one type of effect may in some circumstances appear to be compensatory for the oppositely valenced drug action (e.g., Hinson & Siegel, 1983; Siegel, 1978), in this article we present evidence that both of these effects represent unconditioned, drug- agonistic actions; neither is a homeostatic adjustment. In support of this, animals acquire tolerance to both types of drug actions, although tolerance is more marked with respect to opioid depressant effects. Thus, we contend that there is no evidence that compensatory responses (Siegel, 1977), opponent processes (Solomon, 1977), or conditional or unconditional responses constitute the sub- strates of tolerance development to opioid drugs.

Cardinal Features of Morphine Tolerance Development: Congruence With Behavioral

Models of Tolerance

Tolerance Development With Unsignaled Drug Delivery

Almost all tolerance research prior to that of Mitchell and his colleagues in the 1970s can be characterized by inattention to the

effect of environment on tolerance development. When surveying this literature it is difficult to ascertain the extent to which a tolerance phenomenon derives from signaled as opposed to unsignaled drug delivery. Therefore, it is unknown whether the characteristics of tolerance elucidated by this research apply to tolerance developed through associational or nonassociational mechanisms. This problem is especially serious if one assumes that tolerance phenomena conform to qualitatively different developmental principles depending on the presence of reliable drug cues.

One question initially raised by Siegel's research was whether all tolerance phenomena could be explained by associational mechanisms. In much of Siegel's research, environmental contingencies account for all observable tolerance; that is, unsignaled morphine delivery failed to produce morphine tolerance (e.g., Siegel, 1978). Thus, it seemed possible that previous reports of morphine tolerance (if not tolerance to other drugs) could be accounted for by the inadvertent association of drug with salient cues. Research has shown that manipulation of such subtle cues as the injection ritual or brief context exposure may affect the rate of acquisition of morphine tolerance (Advocat, 198 la, 198 lb).

Data now indicate that associational mechanisms per se cannot account for all instances of morphine tolerance. Tiffany and Baker (198 l) found that animals that were exposed to the tolerance test apparatus (an automated flinch/jump apparatus) only during drug administration displayed significantly more analgesic tolerance than did other groups. Os- tensibly, the flinch/jump apparatus served as a CS signaling morphine effects. However, we also found that animals for which morphine and the flinch/jump apparatus were explicitly unpaired also showed some tolerance development to the 5-mg/kg morphine dose. Moreover, in two separate experiments, Tif- fany and Baker (1981) found evidence of substantial tolerance to the analgesic effects of 20-mg/kg doses when rats had no reliable drug signals. For instance, animals developed tolerance even though they were habituated to the injection ritual, pretested in the flinch/ jump apparatus (latently inhibiting the test apparatus as a CS), and received drug in the


home cage so that the flinch/jump context could not serve as a drug signal. In general, the results of this series of experiments suggest that tolerance can develop when low or moderate morphine doses are delivered in the absence of predictive drug cues, and that higher doses may produce more of this nonassociational tolerance than do low doses.

The proposition that animals acquire tolerance to morphine, independent of Pavlovian contingencies, received additional support in a study by Seaman (in press). The principal goal of this research was to analyze tolerance that developed when drug was delivered in the absence of predictive drug cues. Therefore, Seaman minimized the temporal contiguity between drug effects and salient experimental manipulations: Animals were given tests of nociception (hot-plate tests) prior to any drug delivery, morphine was administered through the indwelling jugular catheters to reduce delivery cues, and, during tolerance development, animals were not exposed to the test apparatus while drugged. During tolerance development, groups received one of four morphine doses, 5, 10, 20, or 40 mg/kg, over 6 dosings. Dose level was completely crossed with four different IDIs: 8, 24, 48, and 120 hr. Results clearly showed that tolerance magnitude was positively related to dose size and negatively related to IDI.

Rate of Tolerance Development

There is copious evidence suggesting that animals acquire tolerance more rapidly when drug administration is uniquely paired with salient environmental cues than when it is not. Much of this evidence derives from the observation that, at the end of a tolerance development phase, animals receiving signaled drug delivery are tolerant, whereas little tolerance accrues in animals receiving a similar course of unsignaled drug delivery (e.g., Siegel, 1975, 1977; Tiffany & Baker, 1981). Of course, these data only reveal a difference in magnitude of tolerance at the end of a drug delivery phase, and do not provide direct evidence of rate differences. Thus, differences in levels of tolerance could be due to a lower ceiling on tolerance development when drug is unsignaled, rather than due to a difference in rate of acquisition.

There are surprisingly few data regarding the rate of tolerance development among rats receiving signaled and unsignaled drug delivery. However, a series of experiments with rats as subjects (Martin, Tiffany, & Baker, 1984; Tiffany, Petrie, Martin, & Baker, 1983) yielded clear evidence that drug signaling produces a more rapid rate of tolerance development to the analgesic effects of morphine. These studies showed that rats receiving morphine, signaled by a distinctive context usually showed analgesic tolerance by the second drug administration. Rats receiving unsignaled drug delivery typically showed no tolerance until the third or fourth drug administration.

The three behavioral tolerance models differ in their ability to account for the results just presented. Siegel's model is able to account for the rapid acquisition of tolerance by animals receiving signaled drug administration but does not account for the tolerance observed in animals receiving unsignaled drug. The opponent-process model is unable to account for the effect of a drug signal on the rate of tolerance development. Solomon (1977, p. 78) is quite clear that the strengthening of b-processes depends on three factors: the interstimulus interval, UCS intensity, and UCS duration. Obviously, these three factors were the same for animals receiving signaled and unsignaled drug; hence their differing rates of tolerance development are inconsis- tent with opponent-process theory. Moreover, as Solomon (1980) himself noted, the opponent-process model cannot explain why a drug-paired context is only associated with b-processes (i.e., tolerance) and not with initial drug effects (i.e., a-processes such as analgesia).

The habituation model predicts the greater acquisition of tolerance by animals given signaled, as opposed to unsignaled, drug administration. To use Wagner' s (1979) termi- nology, a salient predrug cue elicits associatively generated priming of a drug's stimulus properties, which results in more rapid tolerance acquistion than when drug is unsignaled. As noted, the influence of drug signals on tolerance development is likely to be especially great when drug delivery parameters mitigate against self-generated priming (i.e., long IDIs, low doses).


Dose Effects

Most studies examining the effects of dose on tolerance development suggest that dose is positively related to rate and magnitude of tolerance acquisition. For instance, Kayan, Ferguson, and Mitchell (1973) found that, among rats receiving I l days of morphine treatment, animals that received 10-mg/kg morphine displayed greater analgesic tolerance than did animals receiving 5-mg/kg per day, when each group was tested with their respective treatment doses. However, the relationship between dose and morphine tolerance acquisition requires additional investigation. In many studies dose effects have been confounded with manipulations of other variables such as IDI (e.g., Fernandes et al., 1977). In addition, there is a problem in selection of measures used to analyze tolerance development as a function of dose: Animals.are often compared either on the basis of response to a standard test dose or on response to their respective tolerance doses. The former strategy requires that some animals experience a dose change from tolerance development sessions to the tolerance test; the latter requires that groups not receive a standard test dose, rendering comparison difficult. Perhaps the best solution to this problem is to administer a variety of doses on the tolerance test and construct dose-response curves for the groups that received different doses during tolerance development. When this has been done, results generally support the notion that increased tolerance-development doses produce greater amounts of tolerance (i.e., greater shifts in dose-response curves) on test days. For instance, Mucha et al. (1979) found that morphine treatment produced a shift in the log-dose-response curve to the right on the tail-flick test as a positive function of treatment dose (0, 7.5, 15, 25, & 45 mg/kg). Thus, rats that had received 25- or 45-mg/kg morphine during tolerance development re- quired significantly higher test doses to produce the same level of analgesia as was found in rats receiving smaller tolerance-development doses. A similar effect was found for latency to achieve maximal hyperthermia. These findings were not due to differences in rate of tolerance acquisition as the authors conducted tolerance tests only after tolerance

levels were asymptotic. These results do not reveal whether dose affects associative and nonassociative tolerance development differ- ently.

As noted earlier, Seaman (in press) conducted one of the few investigations in which the influence of environmental context on tolerance development was purposely reduced. In that study, rats were administered one of four different morphine doses (5, 10, 20, or 40 mg/kg) and were tested for analgesia with a single 20-mg/kg dose on the hot-plate test. Results clearly showed that the higher tolerance-development doses (i.e., the 20- & 40- mg/kg doses) produced greater analgesic tolerance to the standard 20-mg/kg test dose. Thus, it appears that there is a positive relationship between morphine dose and magnitude of tolerance development when drug is delivered in such a way as to minimize signaling of drug delivery. This conclusion must be constrained somewhat, though, because the tolerance-development phase was relatively brief and these test results may reflect differences in rate of tolerance development and not differences in absolute magnitude.

Some data suggest that magnitude of tolerance following signaled drug delivery does not share a simple positive relationship with dose. In general, these data indicate that, whereas magnitude of nonassociative tolerance increases with dose, the proportion of tolerance attributable to associative mechanisms decreases. Admittedly, it is difficult to ascertain exactly what portion of an observed instance of tolerance is due to associative mechanisms. However, it does appear to be the case that environmental manipulations such as drug-context contingencies exert relatively smaller effects at moderate or high doses than at low doses. A variety of data support this hypothesis (e.g., Sklar & Amit, 1978; Tiffany & Baker, 1981).

In one recent study (Baker & Tiffany, 1984), rats were given either 0 (saline)-, 5- or 30-mg/kg morphine doses during six conditioning sessions; doses were either paired or unpaired with a distinctive context. During three tolerance tests that began 2 days after conditioning, all rats were exposed to the distinctive context, then received 5-mg/kg morphine doses, and were given tail-flick tests


of antinociception 45 min after distinctive context exposure. Results of this study revealed context effects at both dose levels, as animals that had received either 5- or 30- mg/kg doses signaled by the distinctive context were more tolerant than were animals that had received unsignaled doses. There was also evidence that drug signaling exerted greater effects at low, as opposed to high, tolerance-development doses. Among low-dose animals, the context effect persisted across all three tolerance tests, whereas it had disap- peared among high-dose animals by the third tolerance test. Also, animals receiving unsignaled 30-mg/kg doses of morphine showed significantly greater tolerance across all tests than did animals receiving unsignaled 5-mg/ kg doses. In sum, these results suggest that the impact of drug-cue contingencies becomes smaller as dose increases, relative to the tolerance that accrues when drug is delivered in the absence of predictive signals. This conclusion is in agreement with our previously published work on dose effects on morphine tolerance development (Tiffany & Baker, 1981). It is of interest that in two separate studies Siegel (Hinson & Siegel, 1983; Siegel, Hinson, Krank, & McCully, 1982) found evidence of tolerance development to unsignaled delivery of high opiate doses, whereas he had never found evidence of tolerance development to unsignaled low doses (e.g., Siegel, 1977).

In summary, it seems that when cued or uncued drug administration is employed, there is a positive relationship between dose level and tolerance magnitude. However, as drug dose increases, the proportion of a tolerance phenomenon attributable to drug- cue contingencies decreases.

How do the major behavioral tolerance models account for dose effects on tolerance acquisition? Because Siegel's model does not really address nonassociational tolerance it is not relevant to findings regarding dose and nonassociational tolerance development. Fur- thermore, if associational mechanisms exert relatively less effect at high as opposed to low doses, Siegel's theory requires revision because a typical Pavlovian model requires that magnitude of CRs and the UCS (drug dose) be positively related and, therefore, associational

tolerance effects and dose should be positively related.

Solomon's opponent-process model is perfectly congruent with the finding that dose and tolerance magnitude are positively related, but the theory does not really address how associational and nonassociational tolerance processes interact. It certainly does not suggest that the rate of growth of tolerance (B states) should be determined by the presence of drug-paired cues. Nor does it suggest that the relative contribution of associational and nonassociational tolerance mechanisms changes as a function of dose level (cf. Solo- mon, 1977).

Habituation research does not provide a complete prototype of the effect of dose on tolerance acquisition. Some studies suggest that stimulus intensity and rate of habituation are negatively correlated (Sokolov, 1963; Thompson & Spencer, 1966). However, as Graham (1973) observed, there is not a simple monotonic function describing intensity-response relationships in habituation. This relationship may vary as a function of response system and index of habituation (e.g., absolute level vs. change scores). However, some ten- tative conclusions are permitted. Given that habituation does occur, that is, given that stimulus intensity is not so great that a defensive response occurs, then there tends to be a direct positive relationship between stimulus intensity and rate of habituation as measured by change scores (e.g., Jackson, 1974).

Much of the research pointing to a negative relationship between stimulus intensity and rate of habituation concerns psychophysio- logical responses to sudden auditory or tactile stimuli (Graham, 1973). Moreover, even with these types of stimuli, this relationship holds only for certain types of measures (Groves & Thompson, 1970). We propose that characteristics of drugs such as their slow onset of action allow animals to habituate to a greater range of intensities than is the case with other sorts of stimuli.

According to our habituation model of tolerance, the proportion of a tolerance phenomenon attributable to contextual contingencies generally declines with increases in tolerance-development doses. This is because


high doses (a) should lead to greater self- generated priming with a corresponding decrement in the acquisition of associatively generated priming, and (b) are more likely than are low doses to produce prolonged maintenance of a drug's properties in the memory, register. If a representation of the drug is already primed in memory, a subsequent drug exposure is less surprising and hence less likely to result in rehearsal of the association of drug with concurrent environmental cues. Of course, high doses interfere with associative tolerance development only if IDIs are briefer than the duration of self- generated priming.

It appears that the habituation model is the only extant behavioral model that is able to account for the effects of dose on the rate and magnitude of tolerance development, especially as these variables are influenced by the presence of drug signals.

It is important to establish the effects of dose on the contextual elicitation of tolerance. If conditioned drug effects occur at high doses, it would be important to attend to such factors in clinical interventions for drug abusers. However, the relevance of conditioned drug effects to clinical assessment and treatment would be reduced if it were discovered that their impact was largely restricted to low doses. Also, this latter finding would cast doubt on the notion that conditioned drug- antagonistic processes (compensatory responses) subserve major withdrawal signs and symptoms (Hinson & Siegel, 1980).

Interdose Interval, Drug Signals, and Tolerance Retention

Again, as with dose research, investigators examining the effects of IDI on tolerance development have rarely controlled for the presence of drug signals. Thus, it is difficult to ascribe a particular tolerance phenomenon to associational versus nonassociational tolerance-development processes. However, data do exist that permit us to draw some rather firm conclusions.

Studies on tolerance development with chronic morphine administration support the involvement of two qualitatively different processes. On the one hand are data that indicate that maximal levels of morphine

tolerance are achieved only with short IDIs; on the other hand are studies showing that tolerance is not adversely affected by quite long IDIs, or even that long IDIs promote tolerance development.

As with dose, data collected by Seaman (in press) provide important information on the effect of IDI on tolerance development in the absence of reliable drug signals. As noted previously, Seaman's results showed that there was an inverse and linear relationship between IDI and tolerance magnitude. Results col- lapsed across dose levels showed that the 8- and 24-hr IDIs produced similar, high levels of tolerance as assessed by the hot-plate test, whereas the 120-hr IDI yielded very little tolerance.

When morphine delivery is signaled, however, a different pattern emerges. Kayan et al. (1969) compared tolerance development when morphine (5 mg/kg) was administered daily, every 3 days, or at weekly intervals. At each IDI, some rats received drug in the hot-plate testing apparatus, whereas other animals were merely given drug in the home-cage environment. Interpretation of the different IDIs is compromised in this experiment because IDI is confounded with number of morphine administrations and number of hot-plate tests: Rats receiving daily injections were given a total of 12 morphine doses, whereas the 3- day and weekly dose interval groups received a total of 10 and 15 doses, respectively. Despite the confounds in this research, some conclusions are possible. All rats receiving morphine paired with hot-plate tests acquired similar levels of tolerance despite the fact that animals receiving drug at weekly intervals had a longer IDI and fewer morphine doses than did other animals. However, there was evidence in this research that longer IDIs did interfere with tolerance development when drug was administered in the absence of contingent cues (although cf. Kayan et al., 1969, Experiment 4).

Mushlin, Grell, and Cochin (1976) conducted a study in which rats received 15-mg/ kg morphine doses uniquely paired with the hot-plate analgesia assay. Rats received five morphine doses at either l-, 2-, 3-, 7-, 10-, 14-, or 21-day intervals. Results showed that animals at all dose intervals developed signif-


icant amounts of tolerance and that rats receiving drug at the 1- and 2 l-day intervals did not differ in rate or in magnitude of tolerance development. In sum, the results of research conducted by Kayan et al. (1969) and Mushlin et al. (1976), considered in light of Seaman's (in press) research, suggest that tolerance development is relatively unaffected by long IDIs when drug delivery is signaled, but is attenuated when drug delivery is unsignaled.

Single-dose tolerance studies support the notion that the presence of contingent drug cues reduces the disruptive effects of long IDIs on tolerance development. For instance, Kayan and Mitchell (1972) administered two morphine doses at IDIs of 1 day, l week, 4 weeks, 8 weeks, and 6 months. These doses (5 mg/kg) were administered under two different conditions, one in which the first morphine dose was administered in conjunction with hot-plate testing, and one in which the first dose was given in the absence of testing. Results showed that rats with a reliable drug cue (i.e., tested animals) showed significant tolerance 1 day, 1 week, and 4 weeks after a single, low dose of morphine. Rats given drug without a reliable signal did not show tolerance at any IDI. The 4-week retention of tolerance stands in sharp contrast to the more rapid decline of tolerance observed after uncued administration of both large and small amounts of morphine (cf. Lange, Roerig, Fujimoto, & Busse, 1983; Lotti, Lomax, & George, 1966; Rosenfeld & Burks, 1977; Sea- man, in press).

Research done by Kesner (Kesner & Baker, 1981; Kesner & Cook, 1983) supports the following hypotheses: (a) The presence of a drug signal alters the effects of IDI on tolerance development, and (b) signaled drug administration results in greater retention of tolerance than does unsignaled administration. In one study, rats were administered morphine (5 mg/kg) at either 12- or 48-hr intervals. One half of the rats at each IDI were given drug in a distinctive environment, whereas the other half received drug in their home cages. Results clearly showed that the longer IDI retarded tolerance development in the uncued morphine groups but facilitated tolerance development among animals receiving signaled morphine. Moreover, Kesner and

Baker noted that animals receiving signaled morphine retained significantly more tolerance over a 2-week retention interval than did rats that had received drug in the home cage. These results replicate previous findings by Gebhart and Mitchell (1971), who reported that both signaled and unsignaled morphine (5 & l0 mg/kg) produced substantial tolerance to morphine's analgesic effects when drug was delivered at 1-day IDIs. However, when drug was presented at weekly IDIs, only signaled morphine doses resulted in substantial tolerance.

The effects of drug signals and their interaction with IDI suggest an explanation for the anomalous results of certain morphine- tolerance-retention studies. Cochin and Kor- netsky (1964) found that some rats in their studies showed substantial retention of analgesic tolerance 262 days after the end of morphine treatment, which consisted of 70 consecutive days of administration of doses ranging from 20 to 100 mg/kg per day. Even more remarkably, these authors reported that analgesic tolerance to a single 20-mg/kg dose of morphine persisted for as long as 9 months. These results, of course, are in marked contrast to those of numerous other researchers who found rapid decay of tolerance, even after prolonged exposure to drug (Lange et al., 1983; Lotti et al., 1966; Mucha & Kalant, 1980; Rosenfeld & Burks, 1977; Seaman, in press). Cochin and his associates (Mushlin e t al., 1976) were aware of this discrepancy and noted that pellet implantation and infusion both appear to produce tolerance that decays rapidly. He and his collaborators suggested that two qualitatively different types of tolerance exist: a short- and a long-term type. We believe that the short-term variety is merely tolerance that existed through self- generated priming, whereas long-term tolerance is due to retrieval-generated priming. This explanation is consistent with the fact that the short-lived tolerance was associated with infusion and implantation procedures; both produce high steady levels of drug in the body without discrete drug administration signals.

Advocat (1980) produced data consistent with our hypothesis. Advocat observed that spaced, discrete, signaled doses of morphine produced tolerance retention over a 7-day


interval. However, in subsequent research, she noted that tolerance produced by pellet implantation showed a much more rapid decay, even though animals had been im- planted with a 75-mg morphine pellet and were tested repeatedly during tolerance development (Advocat, 1981b). According to the habituation model, the continuous level of morphine intoxication produced by pellet implantation would maintain morphine's stimulus properties in memory and interfere with the association of drug with environmental cues. Therefore, presentation of cues uniquely paired with drug (the tolerance test) would be relatively ineffective in retrieving a drug's stimulus properties into memory.

Of the three behavioral tolerance models presented, only the habituation model is able to account for the effects of IDI and the interaction of these effects with drug-context contingencies. Siegel's model, of course, does not address the issue of nonassociational tolerance. Conversely, Solomon's model is consistent with findings obtained with unsignaled drug administration (e.g., the negative relationship between rate of tolerance development and IDI length), but is not able to account for the fact that drug signals permit tolerance acquisition with long IDIs. Solomon (1977) identified UCS intensity and duration as the only factors other than interstimulus interval that affect strengthening of the b- process (i.e., tolerance). Furthermore, the opponent-process model suggests that tolerance should decay rapidly once drug is no longer presented (Seaman, in press), a finding opposed by the substantial maintenance of tolerance that can occur after a single administration of drug (e.g., Cochin & Kornetsky, 1964). The opponent-process model would be fairly compatible with prolonged retention of tolerance observed after signaled morphine delivery, if it were assumed that conditioning had occurred and the drug signal had become associated with the opponent-process. Yet, again, it is unclear why a drug cue would elicit only the late-onset b-process and not the more temporally contiguous a-process.

The habituation model can account for the results reviewed above because it incorporates the operations of both associational and nonassociational mechanisms. This model has a parallel in other forms of behavioral adapta-

tion. When drug is presented without a salient predrug signal, tolerance acquisition is anal- ogous to habituation to uncued stimulus presentation and conforms to principles derived from traditional habituation research; that is, massed habituation trials (short IDIs) produce more rapid habituation than do spaced habituation trials (long IDIs); Davis, 1970; Gra- ham, 1973). However, when drug is presented contingent with salient signals, tolerance is associatively primed (Wagner, 1979) and, therefore, like other associational phenomena, is relatively impervious to long intertrial intervals (Spence & Norris, 1950). In addition, tolerance retention data are consistent with the operations of both associational and nonassociational mechanisms. In general, given an equal number of Pavlovian conditioning (associational mechanisms) and unsignaled habituation trials, organisms show significantly greater retention of behavior change following Pavlovian learning (Bishop & Kim- reel, 1969; Davis, 1970; Graham, 1973). In the case of tolerance retention, we assume that a drug signal primes the drug's representation in memory, and this inhibits the effects of an immediately subsequent drug presentation. Thus, signaled drug delivery produces greater tolerance retention than does unsig- haled drug delivery (Kesner & Baker, 1981; Kayan & Mitchell, 1972; Kayan et al., 1969; Lotti et al., 1966; Rosenfeld & Burks, 1977; Seaman, in press).

Morphine Tolerance and Homeostatic Mechanisms." Opponent Pro'cesses and Compensatory Responses

According to Siegel's Pavlovian tolerance model, tolerance is due to the acquisition of drug compensatory responses that counter the direct effects of drug. Thus, presentation of drug cues to a tolerant, nondrugged animal should elicit a drug-antagonistic effect (compensatory response). The opponent-process model also stresses that tolerance is due to the development of conditioned and unconditioned drug-antagonistic responses that, theoretically, may be elicited in nondrugged animals (Solomon, 1980). The habituation model, however, suggests that tolerance reflects an insensitivity to drug action, and not the development of homeostatic responses counterdirectional to direct drug effects. Therefore,

94 TIMOTHY B. BAKER AND STEPHEN T TIFFANY

in this section we consider whether tolerance is necessarily associated with the acquisition of drug-antagonistic CRs. Certainly there are numerous examples of drug CRs that are both isodirectional (e.g., Collins & Tatum, 1925; Eikelboom & Stewart, 1979; Sherman, 1979) and counterdirectional (Eikelboom & Stewart, 1982) to a drug's initial actions, but we contend that neither associative nor nonassociative tolerance is dependent on the acquisition of compensatory CRs.

Perhaps the best evidence linking tolerance to a drug-antagonistic CR involves conditioned tolerance to the analgesic effect of morphine. For instance, Siegel (1975) found that after repeated morphine-hot-plate pairings, presentation of the hot plate by itself (paired with NaC1) elicited a hypersensitivity to nociceptive stimulation (hyperalgesia). Sie- gel proposed that this constituted independent evidence of a conditioned drug-antagonistic or compensatory response in drug-free animals. However, whereas there are numerous examples of the enhancement of tolerance development to morphine analgesia through contingent drug signals (e.g., Adams et al., 1969; Kesner & Baker, 1981; Tiffany & Baker, 1981), few researchers have found compensatory hyperalgesic responses in drug-free animals (Krank et al., 1981; Siegel, 1975).

We believe that it is vitally important to demonstrate drug compensatory responses in drug-free animals. Drug compensatory responses constitute independent evidence (i.e., independent of decreased drug effects per se) of a conditioned response that counters a particular drug effect. This type of Pavlovian tolerance model can be contrasted with one in which associative tolerance responses merely involve decreased sensitivity to drug (e.g., receptor insensitivity), which would not necessarily be reflected in the behavior of the drug-free organism. This issue is of practical importance because numerous authors have speculated that drug-antagonistic CRs may trigger relapse in substance abusers (Hinson & Siegel, 1980; Wikler, Pescor, Miller, & Nor- tell, 1971). In fact, some treatment strategies are designed to "extinguish" such drug-antagonistic CRs (Hodgson & Rankin, 1976; cf. Poulos, Hinson, & Siegel, 1981). Also, it would be valuable to obtain compensatory CRs in drug-free animals because this would

allow the investigation of tolerance processes in the absence of drug. The issue is of theo- retical importance because many theorists have suggested that tolerance development is necessarily linked to physical dependence because drug-antagonistic responses constitute the substrate of both of these phenomena (e.g., Hinson & Siegel, 1983; Solomon, 1977). Thus, homeostatic tolerance models have the virtue of accounting for tolerance and dependence with a single mechanism or process.

In the following two subsections of this article (i.e., analgesic response and pyretic/ activity responses), we shall consider both the directionality of drug CRs in animals tolerant to morphine (putative tolerance responses) and evidence that such CRs reflect tolerance mechanisms.

Analgesic response. We have conducted numerous investigations designed to reveal drug-compensatory CRs in tolerant animals tested under saline. We reliably obtain evidence of contextually mediated tolerance in animals given drug, but do not find hyperalgesia in drug-free animals. We have performed six experiments in which we have administered saline to animals in an environment in which context-specific tolerance was obtained (Tiffany, Petrie, Baker, & Dahl, 1983; Zelmer, Tiffany, & Baker, 1984). In every case, these animals show the same nociceptive response as do control animals that never received morphine. For example, in one experiment (Tiffany, Petrie, Baker, & Dahl, 1983), we administered morphine (5 mg/kg) to two groups of rats for five tolerance development sessions. One group had morphine injections in a distinctive flinch/jump test environment, whereas the other group received morphine in the home cage. A third group consisted-of control animals that received saline injections in both environments. During a tolerance test subsequent to the tolerance-development sessions, all animals were given flinch/jump tests of nociception. One half of each group was given morphine in the distinctive test context, whereas the other half received saline injections. A strong context effect was obtained among animals given morphine on the test day, but no differences were evident among the three groups given saline on the test day; that is, the environment previously paired with drug did not elicit any apparent


hyperalgesic compensatory response in non- intoxicated animals.

Other investigators have also failed to find evidence of compensatory responses. For instance, Sherman (1979) found evidence of tolerance to morphine's analgesic effects, and his pyretic measures revealed evidence of a drug-context association. However, Sherman found no evidence of compensatory hyperalgesia when tolerant animals were given saline in the presence of drug cues. There have been other recent failures to find a compensatory response of hyperalgesia despite the presence of contextually mediated tolerance (e.g., Abbott, Melzack, & Leber, 1982). Moreover, Fanselow and German (1982) failed to find a compensatory response of hyperactivity in rats made tolerant to the inactivating effects of morphine. Like us, Fanselow and German obtained evidence of enhanced tolerance development in animals given reliable drug signals, but were unable to observe a compensatory response when tolerant animals were given saline in the presence of drug signals. Finally, Demellweek and Goudie (1983) reported no compensatory response of hyperphagia among rats made tolerant to the anorectic effect of amphetamine.

Our failure to find a compensatory response of hyperalgesia is troublesome given Siegers observations of such responses (Krank et al., 1981; Siegel, 1975). At this time we cannot specify why Siegel's results differ from our own. However, we believe that our results indicate that compensatory responses are not integral components of associational tolerance phenomena. We speculate that apparent compensatory responses in Siegers studies are due either to drug-stress interactions (i.e., cross tolerance between morphine and opiate- mediated stress-induced antinociceptions) or to conditioned activity effects (see Mucha, Volkovskis, & Kalant, 1981; Tiffany, Petrie, Baker, & Dahl, 1983).

To review briefly our conclusions in this section: Drug-paired cues can certainly elicit or enhance tolerance in animals given drug. This, of course, is consistent with Siegel's Pavlovian model. However, several studies have shown that contextually mediated tolerance may occur when there is no evidence of compensatory responding in similarly treated drug-free animals. We have suggested

that putative hyperalgesic compensatory responses might be due to stress or activity effects, or a combination of the two.

Pyretic response. Analysis of morphine's pyretic effects is a complex undertaking as it is well-known that morphine's pyretic actions are influenced by a host of variables including restraint, ambient temperature, and dose. Therefore, it is important to take such factors into account when analyzing conditioning processes in this response system.

Siegel (1978) presented evidence that he contends reflects conditioned compensatory responding to morphine's hyperthermic effects. Like other researchers, Siegel found that a low dose of morphine (5 mg/kg) produces hyperthermia in unrestrained animals (e.g., Eikelboom & Stewart, 1979; Martin, Pryzbylik, & Spector, 1977). However, Siegel also found that animals that had morphine repeatedly paired with a distinctive environment showed a consistent decline in hyperthermic responding over the course of l0 drug administrations. Animals with a history of reliable drug-environment pairings given saline in the distinctive environment previously paired with drug, were hypothermic relative to other groups given saline (one of these groups had a history of home-cage morphine administration and the other was a saline control group). Siegel interpreted these data as indicating that rats acquire tolerance to the hyperthermic effect of a low morphine dose and that a conditioned compensatory hypothermia subserves this tolerance.

A number of investigators have failed to replicate Siegel's findings with respect to conditioned temperature effects. For instance, Sherman (1979) also reported that morphine produced hyperthermia in unrestrained animals, but this hyperthermia increased with repeated drug administrations. Furthermore, this increase, or sensitization, was greatest in animals receiving reliable drug-context pairings. Thus, instead of a conditioned hypothermic response to morphine administration, Sherman found a hyperthermic CR. More- over, when these animals were administered saline in an environment previously paired with drug, they displayed a significant hyperthermia relative to other groups. Other researchers have found that the usual condi-


tioned or unconditioned response to repeated morphine injections is enhanced hyperthermia or hyperthermic response that occurs earlier after a morphine administration (e.g., Gunne, 1960; Lal, Miksic, & Smith, 1976; Mansfield, Wenger, Benedict, Halter, & Woods, 1981; Roffman, Reddy & Lal, 1973). Siegel's results are unique in that they show a large decrease in hyperthermia over repeated administrations of a low dose of morphine.

A comparison of the procedures used by Siegel (1978) with those used by researchers reporting an enhanced hyperthermic response to repeated morphine administration (Mans- field et al., 1981; Sherman, 1979), suggests an explanation for the divergent findings. As Sherman noted in his article, saline-treated animals in the Siegel studies consistently displayed marked hyperthermic responses. In Siegel's research, rats were given 13 temperature assessments after drug or saline injection. These entailed rectal probing and restraint, manipulations known to produce thermic changes in both drugged and drug- free animals (e.g., Blasig, Hfllt, Bauerle, & Herz, 1978; Martin et al., 1977; Stewart & Eikelboom, 1981). In contrast to Siegel's experimental procedures, Sherman used only three temperature assessments, whereas Mans- field et al. used one. In addition, Mansfield et al. habituated animals prior to tolerance development. Stewart and Eikelboom ( 1981) have shown that such handling preexposure atten- uates the stressful effect of subsequent temperature assessments in both drugged and drug-free animals.

In a series of investigations, we examined the change in pyretic response to repeated dosings of morphine under conditions of high and low stress (Zelman et al., 1985). The only difference between the high- and low- stress conditions was that in the high-stress condition, animals received numerous rectal- temperature probings (i.e., 11 or 12 depending on the study), whereas in the low-stress condition animals received few probings (i.e., 3- 4). The results of this research, performed at two dose levels (5 & 35 mg/kg), clearly show that a series of 10 morphine doses results in decreased hyperthermic responding over sessions only when morphine is presented in the presence of high stress. Because animals given

saline under high stress showed temperature decreases across dosings comparable to those shown by morphine-treated animals, Zelman et al. (in press) attributed the declines in both groups to adaptation to temperature-assessment stress per se. Finally, when animals were given saline in an environment previously paired with morphine, there was no evidence of a compensatory, or drug-antagonistic, response.

The results of research on morphine-induced hyperthermia suggest that animals do not become tolerant to this drug effect within the parameters of drug administration used by Siegel (cf. Clark & Bernardini, 1982; Rosow, Miller, Poulsen-Burke, & Cochin, 1982; Rudy & Yaksh, 1977). Animals are able to form an association between the pyretic effects of drug and the context of drug administration, but the CR is isodirectional to morphine's initial effects (hyperthermia), rather than compensatory (Eikel- boom & Stewart, 1979; Sherman, 1979). These results suggest that morphine-induced hyperthermia is probably not a good response to study if one is interested in tolerance development.

Morphine produces hypothermia, as opposed to hyperthermia, if a high dose is used (Numan & Lal, 1981), if animals are re- strained (Martin et aL, 1977) or if drug is delivered at temperatures substantially below thermoneutrality (Paolino & Bernard, 1968). In contrast to hyperthermia, animals quickly become tolerant to morphine-induced hypothermia. Although morphine may initially. produce a profound hypothermia, this is rapidly supplanted by hyperthermia over iterative morphine dosings (Gunne, 1960; Nu- man & Lal, 1981). This is, at least superfi- cially, consistent with a Pavlovian or opponent-process tolerance model in which an initial drug effect (hypothermia) is gradually antagonized by an oppositely valenced response (hyperthermia).

A close examination of the development of tolerance to morphine-induced hypothermia fails to support a homeostatic tolerance model. It is true that tolerance to morphine's hypothermic effects is enhanced by the signaling of drug by salient cues. However, as in the case of analgesic tolerance, the en-


hancement of tolerance by drug signals cannot be attributed to the elicitiation of drug-antagonistic or drug-compensatory responses (Shapiro, Dudek, & Rosellini, 1983). More- over, morphine-induced hyperthermia should not be considered a compensatory response for two compelling reasons: (a) Hyperthermia is evident at low drug doses--doses too low to produce any initial hypothermia (e.g., French, 1979; Thornhill, Hirst, & Gowdy, 1978); therefore, there is no hypothermia for which animals must compensate. (b) Animals do eventually develop tolerance to morphine- induced hyperthermia. Such tolerance development requires that animals be exposed to high doses of drug for long time periods (Clark & Bernardini, 1982; Rosow et al., 1982; Ruby & Yaksh 1977), but the fact that such tolerance occurs underscores the notion that morphine-induced hyperthermia is not a compensatory response.

Our confidence in the above conclusions is buttressed by the fact that morphine's activating effects provide a natural replication of its pyretic actions. Morphine produces a variety of excitatory (hyperthermia, hyper- activation) and depressant (hypothermia, hypoactivity) effects that show the same general pattern with respect to tolerance development (cf. Tatum et al., 1929; Villareal & Castro, 1979). Activity measures reveal that morphine reliably produces initial hypoactivity that is followed by hyperactivity (e.g., Babbini & Davis, 1972; Martin & Papp, 1980; Vasko & Domino, 1978). Rats rapidly develop tolerance to morphine's initial hypoactivating effects, whereas its hyperactivating effects often increase with repeated administration. More- over, consistent with a Pavlovian tolerance model, it is morphine-induced hyperactivity, not hy

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