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Pharmacology Biochemistry and Behavior, Vol. 59, No. 1, pp. 117, 1998 1998 Elsevier Science Inc.

Printed in the USA. All rights reserved0091-3057/98 $19.00 .00

PII S0091-3057(97)00047-6

1

A Two-Separate-Motivational-SystemsHypothesis of Opioid Addiction

ANTOINE BECHARA,* KARIM NADER AND DEREK VAN DER KOOY1

*Department of Neurology, College of Medicine, University of Iowa, Iowa City, Iowa 52242Neurobiology Research Group, Department of Anatomy and Cell Biology, Faculty of Medicine, University

of Toronto, Toronto, Ontario M5S 1A8, Canada

Received 10 November 1995; Revised 13 November 1996; Accepted 31 December 1996

BECHARA, A., K. NADER AND D. VAN DER KOOY. A two-separate-motivational-systems hypothesis of opioidaddiction. PHARMACOL BIOCHEM BEHAV 59(1) 117, 1998.There has been a long debate as to whether opioids aresought for withdrawal relief or for their ability to serve as incentives in their own right. We suggest that independent motiva-tional systems mediate the rewarding effects of opioids in the nondependent state and in the physically dependent/withdrawalstate. In the opioid-dependent state and the presence of opioid withdrawal, the rewarding effects of withdrawal relief inhibitor mask the acute rewarding effects initially exerted in the nondependent state, but the acute rewarding effects are unmaskedafter the alleviation of withdrawal. 1998 Elsevier Science Inc.

Place conditioning Mesolimbic dopamine Tegmental pedunculopontine nucleus Motivation WithdrawalOpiates Addiction Drug dependence Review

VARIOUS models have been applied to the phenomenon ofcompulsive drug use but most emphasize one of two possibili-ties. The first attributes drug motivation, especially with drugsthat produce physical dependence such as opioids, to the needto alleviate the withdrawal distress resultant from a history ofdrug use (54). The other incentive possibility stresses druglikerather than drug withdrawal states as the most powerful insti-gator of drug use, and drug motivation occurs in the absenceof withdrawal and independent of any drug history (116,135).

The view that withdrawal and physical dependence are theprime instigators of opioid intake was challenged by an incen-tive motivational view (116,135) for several reasons. First, thewithdrawal view did not explain why drug self-administrationhabits get established in initially nondependent humans (138)and animals (15,116). Second, the relief of withdrawal distressis only minimally effective in treating addictive syndromes inclinical settings (19,39,122,132), although it may be difficult torelieve withdrawal completely. Third, proponents of the in-centive view argue that the self-administration of drugs gener-ally occurs when the drug stimulus is still present in the brain

rather than when the last drug injection is fully metabolizedand the withdrawal condition is fully established (116).

Although the evidence that withdrawal and physical de-pendence are not necessary conditions for opioids to besought and self-administered is substantial (116,135), the pos-sibility that withdrawal may be a sufficient condition for themaintenance of opioid administration in physically dependentsubjects has never been ruled out. Indeed, there is a strong ev-idence in support of the view that once an opioid addict be-comes physically dependent, tolerance may develop to theacute rewarding properties of opioids, and the primary deter-minants of continued opioid use become the avoidance or ter-mination of drug abstinence (50,64,67,84,131). Heroin is ini-tially sought by human drug users for its incentive motivationalproperties, which are presumably associated with the high andeuphoria experienced after acute administration of the drug(84). However, when allowed chronic unlimited access to opi-oids, human addicts begin to administer progressively largerdoses of opioids and eventually develop a dependence syn-drome characterized by the expression of characteristic so-

1 To whom requests for reprints should be addressed.

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2 BECHARA, NADER AND VAN DER KOOY

matic withdrawal signs with abstinence from opioids (50,84).Furthermore, they begin to report fewer highs and becomemore concerned with terminating abstinence and avoidingwithdrawal (84).

Thus, even in the case of the most studied class of drugs(opioids), an incentive motivational view by itself does not ac-count for the powerful rewarding properties of opioids associ-ated with their ability to alleviate the aversiveness of withdrawalin physically dependent humans and animals (10,56,83,84).We acknowledge that proponents of the incentive view of opi-oid motivation do not deny that withdrawal is a motivatingfactor in opioid-dependent animals, but they assert that, in theglobal phenomenon of opioid addiction, withdrawal plays asecondary role in opioid motivation. Similarly, proponents ofthe withdrawal view do not dismiss the importance of the re-warding properties of opioids in nondependent animals, butthey stress that withdrawal becomes the primary mechanismunderlying the motivation for opioids once animals are ex-posed to opioids. Thus, the idea that opioid motivation stemsfrom the ability of opiates both to elicit incentive reward andto alleviate withdrawal is not new. However, no theory has yetexplained when incentive reward or aversive withdrawal be-comes more or less important, and how much does reward vs.withdrawal contribute to opioid motivation. For example,could there be some subtle mechanisms of opioid withdrawalin the nondependent state that contribute to opioid motiva-tion? If so, how much is that contribution? At what stage doanimals switch from a nondependent to a dependent state?When animals become dependent, does incentive reward stillplay a primary role? We propose a two-motivational-systemshypothesis of opioid addiction that addresses these questionsand helps account for many of the instances of opioid rewardthat are not explained by contemporary theories of opioid ad-diction. This proposal has emerged from several studies thatwere carried out on the neurobiological substrates mediatingthe motivational effects of opioids (4,5,7,8,10,75). In the fol-

lowing sections, we present the experimental evidence leadingto the formulation of our two-motivational-systems hypothesis.

ASSESSMENT OF DRUG MOTIVATION

Because the history of drug intake is an important variablein the study of opioid motivation in the dependent vs. nonde-pendent state, we have employed the place conditioning para-digm. In this paradigm, the rewarding effects of opioids can bedemonstrated in nondependent animals after minimal expo-sure to the drug (71,73,125), thus minimizing the developmentof dependence/withdrawal effects that result from repeatedexposures to opioids. With the same paradigm, animals thathave been chronically exposed to opioids still can be assessedfor their motivation for opioids in the dependent state.

Many workers in the field on drug motivation assume thatthe most suitable paradigm for studying drug motivation is theintravenous drug self-administration paradigm. In this re-spect, we stress the fact that the notion of independent mech-anisms underlying the motivation for opioids in the opioid-nondependent vs. the opioid-dependent state would havebeen difficult to address in the absence of place conditioningand its exquisite temporal control of the pairing of condi-tioned stimuli with history of drug use (10). Furthermore,given that specific neural manipulations block differentclasses of motivated behaviors as assessed by place condition-ing, it is possible to predict how the same neural manipula-tions would affect the self-administration of opioids. The dis-crepancies that result among the different paradigms do not

necessarily mean that these paradigms are inherently incom-patible. The discrepancies may be the by-product of differentstates (nondependent vs. dependent and withdrawn) underwhich animals are tested in the different experimental para-digms.

TERMINOLOGY

In the following sections, we describe the various phases ofopioid-seeking by using standard terminology used in the Di-agnostic and Statistical Manual of Mental Disorders, 4th edi-tion (DSM-IV). However, in the Definitions and Predictionssection, we reconcile this terminology with our proposed be-havioral and neurobilogical criteria, which define similar in-stances of opioid-seeking in animal models.

In the DSM-IV, withdrawal is defined as a maladaptivebehavioral change, with physiological and cognitive concomi-tants, that occurs when blood or tissue concentrations of asubstance decline in an individual who had maintained pro-longed heavy use of the substance (DSM-IV, p. 178). In ourdiscussion, we refer to the aversive state associated with thistype of withdrawal as the aversive effects of withdrawal. Whenunpleasant withdrawal symptoms and signs develop, the per-son tends to seek the substance to relieve or avoid thosesymptoms (DSM-IV, p. 178). We refer to the reward associ-ated with the alleviation of these withdrawal symptoms andsigns as the rewarding effects of withdrawal relief.

Many investigators have argued that withdrawal can bepresent after a few injections of opioids or precipitated by anopioid antagonist administered even after a single exposure toan opioid agonist (1,2,22,46,52,66,102,130,137). Because thiswithdrawal phenomenon is detectable only when using highlysensitive techniques, it is important to distinguish this type ofwithdrawal from the physical withdrawal signs observed afterchronic drug use. Thus, many of the investigators cited earlierhave used the term acute withdrawal. In our discussion, we

have adopted this term to denote the type of withdrawal ob-served after a few exposures to opioids.Some individuals show a pattern of compulsive drug use,

without any observed signs of tolerance or withdrawal (DSM-IV, p. 178). However, DSM-IV did not provide a specific termfor the reward associated with this instance of substance use.To distinguish this type of reward from the reward associatedwith withdrawal relief, we use the term acute reward. Otherinvestigators have used the term acute to denote the reinforc-ing properties of psychoactive drugs during their initial use,i.e., prior to the development of physical withdrawal (54).

The TPP as a Critical Substrate for Acute Reward

Investigations aimed at unraveling the neurobiological

substrates underlying the rewarding effects of opioids andother psychoactive drugs have revealed that several neuralstructures localized or connected to the limbic system of thebrain are primary loci for mediating the rewarding propertiesof these drugs (54,116,133,134). Microinjection studies haverevealed that the receptor sites where opioids and stimulantsact to produce rewarding effects in drug-naive rats are in thelimbic forebrain (i.e., nucleus accumbens and lateral hypo-thalamus) and midbrain [i.e., ventral tegmental area (VTA)and periacqueductal gray] (3,21,29,93,124,126,135). In addi-tion, electrophysiological studies have indicated that the re-ward information generated by electrical brain stimulation ofthese forebrain sites is carried through descending pathwaysof the medial forebrain bundle (MFB) to the midbrain (12).

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A HYPOTHESIS OF OPIOID ADDICTION 3

Several lines of evidence now suggest that the tegmentalpedunculopontine nucleus (TPP) of the midbrain is a criticalsite for acute reward from opioids (7,75,85,86,88,89). Lesionsof the TPP, however, do not interfere with the rewarding ef-fects of withdrawal relief by opioids in dependent and with-drawn animals or with the aversive effects of a withdrawalsyndrome in dependent animals (10), both of which are medi-ated by the same mechanism (4,5,79). We suggest that theTPP-mediated rewarding effects of opioids in the nondepen-dent state are wholly due to the acute rewarding effects ofopioids. Anatomical evidence indicates that the TPP region ofthe midbrain and pons receives neuronal inputs from all thestructures identified as sites for eliciting the acute rewardingeffects of opioids via direct monosynaptic or indirect multi-synaptic pathways traveling through the MFB (120,121). Bi-lateral ibotenic acid lesions of the TPP region blocked the ac-quisition, but not retention, of morphine-conditioned placepreferences in animals trained with only a few injections ofopioids (7,87,89). Nondependent rats that had acquired amorphine-conditioned place preference prior to TPP lesionswere capable of retaining and demonstrating these place pref-erences after lesioning the TPP (7). However, after the le-sioned rats were exposed a few times to the same environ-ment, the conditioned preferences were extinguished, and therats were no longer able to re-acquire the place conditioningwith additional injections of morphine (7). These results sug-gest that TPP lesions block the unconditioned, but not theconditioned, acute rewarding effects of opioids. Similar toibotenic acid lesions, bilateral electrolytic lesions placed in themidbrain tegmentum [infringing on the ventromedial area ofthe TPP defined as critical for psychoactive reward (7)] de-pressed bar pressing for electrical stimulation of the septal re-gion (100,101), the lateral hypothalamus (17) and the MFB(74). The TPP itself has low levels of opioid receptors (45,61),and the effects on the acute rewarding properties of opioidsseen after the lesions are most likely due to disruption of an

acute reward circuit after the opioid-receptor-bearing neuron.Furthermore, the TPP-induced block of opiate motivation inanimals trained with only a few injections of opiates suggeststhat the TPP region is critical for acute reward in the nonde-pendent state.

Anatomical evidence shows that the TPP is in a position toinfluence a variety of somatomotor responses because itprojects directly to widespread parts of the brainstem reticu-lar formation (69), the thalamus (40,111), the spinal cord(34,111) and the basal ganglia and associated structures(30,48,98,99,115). Furthermore, the TPP region appears tooverlap the mesencephalic locomotor region, a region that fa-cilitates locomotion when electrically stimulated in the decer-ebrate rat (109). Therefore, we hypothesized that the TPP re-gion of the brainstem may serve as an anatomical substrate

where acute reward signals generated at more rostral levels ofthe brain exit the limbic system and gain access to motor sys-tems that initiate behavioral acts (9). However, other evi-dence using lesions at slightly different TPP loci suggests thatTPP lesions can have differential effects on the reward vs. thecataleptic and excitatory locomotor effects of opioids andstimulants (88).

The notion that the TPP region is critical for mediating theacute rewarding effects of opioids (7,10) does not mean that itis also critical for the properties of these drugs, which exertsubjective sensory effects (50). In rats, morphine may havedistinct cuing or discriminative properties (63). However,these internal cuing effects of morphine were separable fromthe rewarding effects of the same drug. Combined neural and

pharmacological manipulations that blocked the rewardingeffects of opioids in nondependent rats did not interfere withthe discriminative effects of morphine (63). These results sug-gest that the discriminative properties of opioids are neurobi-ologically separable from their TPP-mediated acute reward-ing properties. Infusions of morphine into the parabrachialnucleus (PBN), but not into the VTA, serve as stimuli for theacquisition of discrimination learning, whereas infusions ofmorphine into the VTA, but not into the PBN, produce re-warding effects (49).

Dopamine as a Critical Substrate for the Rewarding Effects ofWithdrawal Relief

Lesions of the TPP region provide a tool for disrupting theneural processes responsible for the acute rewarding proper-ties of opioids, thus allowing an independent assessment ofthe role of withdrawal in opioid motivation in physically de-pendent animals. In our behavioral assays, we rendered ratsphysically dependent after chronically exposing them to mor-phine (60 mg/kg/day for a minimum of 14 days) until they be-gan to show physical signs of a classic withdrawal syndrome(4,5,8,10).

Lesions of the TPP disrupted the acute rewarding effectsof opioids in the nondependent state. However, the lesionsdid not affect the rewarding effects of withdrawal relief in thedependent state (10). Although the TPP region is critical formediating opioid reward, at least in nondependent rats, thereis strong support for the view that the neural function of theneurotransmitter dopamine also is important for opioid re-ward (13,14,114,135). In opposition to this strong dopaminer-gic hypothesis, however, is the evidence that opioid rewardsometimes can occur when dopamine neuronal function iscompletely blocked by dopamine antagonists (27,54,59,110).In light of the finding that the TPP lesions separate the acuterewarding effects of opioids in the nondependent state from

the rewarding effects of withdrawal relief in the dependentstate (10), the effects of dopamine antagonists on the reward-ing effects of opioids in nondependent vs. dependent animalswere explored (4).

Dopamine antagonists blocked the ability of opioids toelicit reward (withdrawal relief) in dependent rats that werein a state of withdrawal but did not interfere with the ability ofopioids to elicit acute reward in nondependent rats (4). Spe-cifically, the conditioned place preferences seen in opioid-dependent and withdrawn rats conditioned with morphine orheroin were blocked by pretreatment with the dopamine an-tagonist alpha-flupentixol or pimozide. The same conditionedplace preferences seen in nondependent rats were blocked byTPP lesions but not by dopamine antagonists (4). Using amodified place conditioning procedure (in which the direct ef-

fects of opioids were paired with one environment without thealternate pairing of another environment with the absence ofmorphine, i.e., withdrawal), opioid-dependent and opioid-nondependent rats acquired preferences for places associatedwith morphine rather than with unfamiliar neutral places (4).In opioid-dependent rats, the preferences for places pairedwith the alleviation of withdrawal by morphine were blockedby dopamine antagonists but not by TPP lesions. In nonde-pendent rats, the preferences for places associated with mor-phine (acute reward) were blocked by TPP lesions but not bydopamine antagonists. We suggest that the dopamine-medi-ated rewarding effects of opioids in the dependent and with-drawn state are due wholly to the reward associated with thealleviation of aversive withdrawal. Thus, the pattern of effects

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produced by dopamine antagonists is exactly opposite to thepattern of effects on opioid reward produced by TPP lesions(4). These results demonstrate a double dissociation of two in-dependent neural systems mediating the rewarding effects ofopioids in the nondependent state vs. the dependent and with-drawn state. Only one subclass of rewarding events, thoseevents associated with the presence of an opioid-dependentstate and withdrawal, appears to depend on the function ofdopamine neurons. Interestingly, similar to the results withTPP lesions in the nondependent state (7), dopamine antago-nists appear to block the unconditioned rewarding effects ofopioids but not the conditioned rewarding effects previouslyassociated with opioids in dependent rats (65). We suggestthat training in extinction (i.e., in the presence of dopamineblockade to prevent unconditioned rewarding effects) is nec-essary to abolish the conditioned rewarding effects of the de-pendence system in dependent rats.

Dopamine as a Critical Substrate for the Aversive Effectsof Withdrawal

Just as the activation of opioid receptors by morphine innondependent vs. dependent rats produces different mecha-nisms of reward, reduced activity on these opioid receptorsproduces different mechanisms of aversion (5). Opiate antag-onists produce clear aversive effects in both morphine-depen-dent (26,33,41) and morphine-naive (6,73) rats. In morphine-dependent rats, opioid antagonists block exogenous andendogenous opioid activity; in morphine-naive rats, opioidantagonists block only endogenous opioid activity. Dopamineantagonists blocked the avoidance behavior of rats to placespreviously paired with naloxone-precipitated withdrawal inopioid-dependent rats, but dopamine antagonists did notblock the avoidance of places paired with naloxone injected inopioid-naive rats (acute withdrawal) (5). TPP lesions did notinterfere with the acute withdrawal effects of naloxone in

morphine-naive rats (5). Opiate-dependent and opioid-non-dependent rats acquired conditioned aversions for places as-sociated with the absence of morphine (i.e., withdrawal).However, the acquisition of these conditioned aversions de-pended on the time of deprivation from morphine (5). That is,opioid-dependent rats acquired the aversions if rats weredepreived of morphine for 16 or 24 h prior to conditioning.Opiate-nondependent rats acquired the aversions at 1116but not at 24 h postmorphine. The aversive effects of with-drawal observed in opioid-dependent rats were blocked bydopamine antagonists (5). The aversive effects of acute with-drawal from a few injections of morphine observed in nonde-pendent rats were not blocked by dopamine antagonists. Theresults suggest that decreases in the actions of endogenousopioids may give rise to a separate endogenous withdrawal

syndrome (acute withdrawal) in nondependent animals (5). Itis not clear why the aversive effects of acute withdrawal ap-pear at 1116 h postmorphine, whereas the aversive effects ofchronic withdrawal appear at 1624 h postmorphine. Never-theless, the differences in time course between acute andchronic withdrawal further illustrate the differences in thetypes of withdrawal observed in the nondependent state vs.the dependent state.

In summary, common mechanisms mediate the aversive ef-fects of spontaneous and naloxone-precipitated withdrawal inopioid-dependent rats because both effects are blocked bydopamine antagonists. Common mechanisms also may medi-ate the aversive effects of spontaneous acute withdrawal andthe aversive effects of naloxone in nondependent rats because

both effects are insensitive to dopamine antagonist blockade.Although dopamine antagonists block the aversive effects ofwithdrawal and the rewarding effects of withdrawal relief byopioids in dependent and withdrawn rats, TPP lesions blockonly the acute rewarding effects of opioids observed in nonde-pendent rats or the acute rewarding effects observed in de-pendent rats that are not in a state of withdrawal (i.e., ratsthat received a maintenance dose of morphine, 20 mg/kg, 3.5h prior to place conditioning with another separate dose ofmorphine, so that during conditioning these rats do not ex-press aversive effects of withdrawal or rewarding effects ofwithdrawal relief). TPP lesions, however, do not block theaversive effects of acute withdrawal observed in nondepen-dent rats (5). These results dissociate a single dependence mo-tivational system for the aversive effects of withdrawal andthe rewarding effects of withdrawal relief, which is dopamine-mediated, from two other processes: a nondependence systemfor acute reward that is mediated by TPP and a nondepen-dence system for acute withdrawal that is hypothesized to bemediated by the arcuate nucleus (5,72).

These results support many previous studies that have sug-gested that acute withdrawal begins with a few or even after asingle exposure to opioids (1,2,22,46,52,66,102,130,137). How-ever, these studies have assumed that the phenomenon ofacute withdrawal represents the initial stages in the develop-ment of a classic withdrawal syndrome. Although some of thesymptoms and signs in acute and classic withdrawal may beparts of the same process, we stress that the aversive mecha-nisms associated with acute withdrawal are fundamentally dif-ferent from those associated with classic withdrawal. Anotherline of evidence that supports this idea comes from studieswith clonidine. Clonidine (an alpha2-noradrenergic agonist)has been implicated in mechanisms of withdrawal for its prop-erties to alleviate signs of withdrawal in rats (16,123,124) andmany of the physical signs and subjective symptoms of with-drawal in humans (31,32,38,51). Therefore, we investigated

the effects of clonidine on the rewarding and aversive effectsof opioids in the dependent and nondependent states. Using aclonidine dose that has no dopaminergic activity, clonidineblocked the rewarding effects of withdrawal relief by opioidsin dependent and withdrawn animals and the aversive effectsof spontaneous withdrawal from morphine in dependent andwithdrawn animals (79). Clonidine did not block the TPP-mediated acute rewarding effects of morphine or the aversiveeffects of naloxone in naive rats (presumably the mechanismunderlying naloxone aversion in naive rats is analagous to themechanism underlying acute withdrawal) (79). The resultsprovide an additional line of support for the idea that theaversive mechanisms associated with acute withdrawal arefundamentally different from those associated with classicwithdrawal. Furthermore, they suggest that dopaminergic and

noradrenergic substrates are linked serially in a neurobiologi-cal system mediating the aversive effects of withdrawal andthe rewarding effects of withdrawal relief by opioids in the de-pendent state.

Lack of Tolerance in the TPP Nondependent Reward System:Apparent Tolerance Is Inhibition or Masking of theTPP System

If the reward mechanism of withdrawal relief, which is me-diated by dopamine, is dominant in the opioid-dependentstate, what happens to the TPP acute reward mechanism inthe nondependent state? Based on tissue biochemical changes,tolerance has been though to be the result of long-term cellu-

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lar adaptation (23). When dependent rats received withdrawalalleviating doses of morphine (as shown by an absence of so-matic withdrawal signs and lack of aversive withdrawal effectsthat are blocked by dopamine antagonists) 3.5 h prior to placeconditioning with morphine, morphine elicited preferences inopioid-dependent rats (no longer in a state of withdrawal)that were blocked by TPP lesions rather than by dopamineantagonists (8). Most important, these TPP-mediated condi-tioned place preferences now expressed in opioid-dependent(and not withdrawn) rats were equal in magnitude to thoseexpressed in opioid-nondependent rats. Such an abrupt andcomplete reinstatement of the TPP-mediated acute rewardingeffects of opioids suggests that the disappearance of theseacute rewarding effects is not due to neural tissue toleranceassociated with long-term cellular adaptation after chronic ad-ministration of opioids. Rather, the alleviation of withdrawalin dependent rats allows the reexpression of the unalteredneural tissue substrates (the TPP-mediated mechanism) sub-serving the acute rewarding effects of opioids. Thus, we hy-pothesize that the behavioral tolerance observed in opioid-dependent rats is due to the inhibition or masking of the acuterewarding effects of opioids (TPP-mediated) by mechanismsassociated with opioid dependence and withdrawal. However,the unaltered, TPP-mediated acute rewarding effects that be-come inhibited or masked by the effects of withdrawal stillcan play a powerful motivational role, even in dependent ani-mals, once withdrawal is alleviated.

Somatic Signs of Opioid Withdrawal Are Not Synonymouswith the Aversiveness of Withdrawal

In animal models of opioid withdrawal, the primary focushas been on the physical aspects of withdrawal (such as so-matic withdrawal signs) as indices reflecting the intensity ofthe aversiveness of withdrawal (11,129). However, animalsbegin to avoid cues associated with the absence of opioids

(i.e., withdrawal) even after they have been exposed to only afew injections of opioids in the absence of any observablesigns of withdrawal (5,75). Although we suggest that this earlyavoidance behavior is associated with fluctuations in endoge-nous opioid activity (i.e., acute withdrawal and not opioid de-pendence), we argue that the aversive effects of this acutewithdrawal phenomenon are mediated by mechanisms thatare different from those of withdrawal in the dependent state.We suggest that at some point this avoidance behavior fromacute withdrawal switches to avoidance based on opioid de-pendence (still at a time prior to the appearance of any signsof somatic withdrawal) (5,75). Therefore, we argue that so-matic withdrawal signs are not the most sensitive indices fordetecting opioid dependence.

There remains a division in the field as to the appropriate

behavioral definition of drug dependence and withdrawal.Some investigators have studied opioid withdrawal in terms ofits directly observable physical manifestations (44), and othershave studied opioid withdrawal in terms of its properties thatproduce conditioned avoidance of environments paired withwithdrawal (41,62,117). However, Mucha (70) found no pre-dictive relationship between the presence of specific with-drawal signs and the aversive effects of withdrawal as assessedby place conditioning procedures. Furthermore, several otherstudies have shown that withdrawal aversiveness is induced bythe central blockade of opioids (41,55,117) and that themethod of place aversion, and not the measurment of thephysical signs of withdrawal, is the more sensitive measure ofthe aversive stimulus properties of opioid withdrawal (41,117).

Thus, several lines of evidence now suggest that the somaticsigns of opioid withdrawal are not the most reliable indices forpredicting the aversive mechanisms that induce conditionedaversive effects (4,5,60,70,117). For instance, rats avoidedcues paired with the absence of opioids (i.e., withdrawal) afterreceiving several injections of high doses of heroin, but theserats did not show any observable signs of somatic withdrawal.This avoidance behavior was blocked by dopamine antago-nists in a manner consistent with the block of the withdrawalavoidance behavior of animals chronically treated with opi-oids (and demonstrating a characteristic somatic withdrawalsyndrome) by dopamine antagonists (75). The neurobiologi-cal mechanisms subserving the somatic signs vs. the aversive-ness of withdrawal must be partly separate because dopamineantagonists blocked the avoidance behavior elicited by spon-taneous morphine withdrawal (4) and naloxone precipitatedwithdrawal (5) in rats chronically treated with morphine (opi-oid-dependent). The same dopamine antagonist treatmentsdid not attenuate the somatic withdrawal signs associated withthe precipitated withdrawal (5). However, clonidine seems toaffect both the signs of withdrawal (16,123) and the avoidanceof withdrawal in dependent and withdrawn animals (79). Suchresults illustrate the difficulties in using somatic signs of with-drawal as indices for the motivation of animals to avoid opioidwithdrawal (5,70,75). Furthermore, a study that directly com-pared the effects of somatic signs of withdrawal vs. the aver-siveness of withdrawal revealed that the conditioned avoid-ance of environments associated with opioid withdrawal wasthe most sensitive behavioral assay of opioid dependence andwithdrawal (103).

Withdrawal Aversiveness in the Dependent State Is Mediatedby a Patterned Dopaminergic Activity

Data on the aversiveness of opioid withdrawal (4,5,75)

with the data presented by Harris and Aston-Jones (44) re-veal an interesting dissociation between the dopaminergicmechanisms that mediate the aversive properties of opioidwithdrawal and the dopaminergic mechanisms that mediatethe somatic signs of withdrawal. Harrris and Aston-Jones (44)showed that systemic alpha-flupentixol precipitated somaticsigns of withdrawal in opioid-dependent rats and that the di-rect dopamine agonist apomorphine reduced the incidence ofthese somatic withdrawal signs in opioid-dependent and with-drawn rats. These data suggest that decreased dopamine re-ceptor activation mediates the somatic signs of withdrawal.However, pretreatment with the dopamine antagonist alpha-flupenthixol did not reduce the incidence of somatic with-drawal signs in dependent rats that were already showingsigns of withdrawal (5). This finding is consistent with the in-

terpretation of Harris and Aston-Jones if one considers thatthe level of dopamine receptor activation is already depresedin dependent and withdrawn rats. However, these samedopaminergic manipulations had different effects on the aver-sive effects of opioid withdrawal. Pretreatments with either al-pha-flupentixol (4,5) or the direct dopamine agonist apomor-phine (77) blocked the acquisition of place aversions toenvironments associated with opioid withdrawal in dependentanimals. Furthermore, pretreatment with the indirect agonistamphetamine, which can both increase the signal-to-ratio ofpostsynaptic striatal cell activity (42) and potentiate dopa-mine release from nerve terminals (128), had no effect on theacquisition of conditioned place aversions to environments as-sociated with opioid withdrawal (77).

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If the aversive effects of opioid withdrawal in the depen-dent state were mediated by an absolute decrease in dopa-mine receptor activation, then both amphetamine and apo-morphine would have raised the dopamine receptor activityand decreased the avoidance of places associated with opioidwithdrawal. Conversely, if dopamine activity was maximallydepressed in opioid-withdrawn rats, then alpha-flupenthixolshould not have blocked these aversions. The findings with di-rect and indirect dopaminergic agonists and antagonists arguethat the aversive effects of opioid withdrawal in the depen-dent state are mediated by a patterned activation of postsyn-aptic dopamine receptors. Thus, two different dopaminergicmechanisms mediate the somatic and aversive withdrawalproperties of opioid withdrawal.

DEFINITIONS AND PREDICTIONS

In the previous sections, we used terms to describe differ-ent phases of opioid-seeking that were either defined in theDSM-IV or previously used by investigators in the field. Inthis section, we attempt to reconcile this terminology with ourhypotheses and redefine these terms based on behavioral andbiological criteria used in experimental animal models of ad-diction. Furthermore, we make explicit predictions about theneurobiological substrates of the different phases of opioid-seeking.

Given the evidence presented in the previous sections, wedefine withdrawal in rats with chronic exposure to opioids interms of avoidance of cues paired with the absence of opioids(i.e., withdrawal) after at least 16 h of opioid abstinence. Wepredict that this avoidance behavior is blocked by dopamineantagonists. We define acute withdrawal in terms of avoid-ance by rats of cues associated with the absence of opioids af-ter 1116 h of morphine abstinence. We predict that thisavoidance behavior is insensitive to blockade by dopamineantagonists (5). However, we define the reward of withdrawal

relief in animals chronically exposed to opioids and in a with-drawal state in terms of approach of cues paired with opioids.We predict that this approach behavior is blocked by dopa-mine antagonists. We define acute reward in terms of the ap-proach of opioid-paired cues in the absence of withdrawal.We predict that this approach behavior is blocked by TPP le-sions. Consequently, opioid dependence is defined as a state inwhich aversive withdrawal and the reward of withdrawal re-lief exist without necessarily being expressed. For example,opioid-dependent animals that have undergone a sufficientnumber of hours of abstinence from morphine will expressaversive effects of withdrawal and rewarding effects of with-drawal relief and therefore are described as opioid dependentand withdrawn. Opiate-dependent rats that have just receivedopioids for alleviating withdrawal will not express aversive ef-

fects of withdrawal or rewarding effects of withdrawal reliefand therefore are described as opioid dependent, but not inwithdrawal. Conversely, opioid nondependence is defined as astate in which withdrawal and withdrawal relief are neverpresent. Animals that are in a nondependent state show onlyacute rewarding effects. At some point (after a few exposuresto opioids), animals may begin to show aversive effects ofacute withdrawal. Although these aversive effects of acutewithdrawal may be sufficient for opioid-seeking, we believethat they are not necessary for opioid-seeking. In the absenceof the TPP, the acute rewarding effects of opioids are neverobserved (5). However, in the absence of the arcuate nucleusof the hypothalamus (hypothesized to be a critical site for me-diating the aversive effects of acute withdrawal), the acute re-

warding effects of morphine in nondependent rats are not al-tered (72).

We admit that these behavioral definitions are somewhatcircular in that they partly arose from and depend on neurobi-ological manipulations to help characterize the putative moti-vational processes. However, one possible way of breakingthe inherent circularity in definitions of motivation is to eluci-date the underlying neural mechanisms that support moti-vated behaviors that are defined based on operational crite-ria. Once the neural substrates have been identified, one maywork back up to behavior and identify those behaviors or as-pects of behavior that are affected by manipulations of thesesites. Through this interplay between levels of analysis (a typeof bootstrapping method), one may eventually arrive at anoncircular behavioral definition of motivation that is notstrictly operationally based. Thus, the most parsimonious res-olution to this problem would be the identification of a singleneural substrate that mediates both the motivational and be-havioral expressions of a single intervening variable. Thisbootstrapping method has already proven valuable in refutingthe criticism of triviality. New models of motivation can ex-plicitely separate different types of motivation on both a neu-robiological and behavioral level. The existence of separatemotivational systems producing different behavioral effectsdemonstrates that these motivational processes are nontrivial.Thus, an approach based on an interplay between the behav-ioral and neurobiological levels of analysis could confer thetheoretical framework of motivation with greater validitythrough correlation with physiological and anatomical data.Ignoring Skinners suggestion that psychologists not physiolo-gize (i.e., define behavioral terms on a neural level), most mo-tivational researchers have looked to neurobiology to evadethe problems of motivational concepts being circular and trivial.

THE TWO-MOTIVATIONAL-SYSTEMS HYPOTHESIS

To account for all the different instances of opioid rewardand withdrawal discussed thus far, we propose a two-motiva-tional-systems hypothesis for opioid addiction that is based onthe distinction between two conditions: an opioid-dependentand an opioid-nondependent state. The motivational mecha-nisms operating in the two conditions are subserved by inde-pendent neurobiological substrates.

We hypothesize that there are two different mechanisms ofreward. The first mechanism is best demonstrated in the non-dependent state, in the absence of any evidence of depen-dence and withdrawal. A critical neural substrate subservingthis mechanism of reward is the TPP region of the brainstem.In the nondependent state, the primary mechanism underly-ing the motivation for opioids is their acute rewarding proper-

ties. The TPP-mediated reward also is expressed in the opi-oid-dependent state if animals have just received a withdrawalalleviating dose of opioids and are no longer in a state of with-drawal.

The second reward mechanism is best demonstrated in theopioid-dependent state, in the presence of dependence andwithdrawal. A critical substrate subserving this mechanism ofreward is dopaminergic neurons. The dopamine-mediated re-ward is expressed in dependent animals that undergo severalhours of deprivation from opioids (at least 16 h) at the sametime when the aversive effects of withdrawal are expressed.Thus, in an opioid-dependent and withdrawn state, the pri-mary mechanism underlying the motivation for opioids is thereward associated with the alleviation of withdrawal by opi-

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oids. If animals were opioid-dependent but not in a state ofwithdrawal (i.e., animals had just received opioids for with-drawal relief), then the TPP-mediated reward system (acutereward) becomes the primary motivating factor. After chronicexposure to opioids and the development of opioid depen-dence, the TPP-mediated reward system does not become tol-erant but only inhibited or masked by the mechanisms ofwithdrawal in opioid dependent rats. Alleviation of with-drawal can unmask the TPP system and reinstate the ability ofthe TPP to mediate acute reward, even in the opioid-depen-dent state.

Distinct behavioral mechanisms of withdrawal also exist inthe nondependent and dependent states. In the nondepen-dent state, acute withdrawal may develop even after a few in-jections of opioids. The aversive effects of these acute with-drawal mechanisms are independent of the TPP. The neuralsubstrates subserving the aversive effects of these acute with-drawal mechanisms remain uncertain, but the arcuate nucleusof the hypothalamus is a likely candidate. In the absence ofthe TPP, we do not know whether these mechanisms of with-drawal can by themselves instigate approach (reward) of opi-oids. However, the aversive effects of withdrawal from opioidsin the dependent state are very significant. These aversivewithdrawal mechanisms are mediated by dopamine, and theyare inseparable from the rewarding effects of withdrawal re-lief by opioids. Whenever these aversive withdrawal mecha-nisms are expressed, the acute reward and acute withdrawaleffects of the nondependent state become inhibited ormasked. Whenever these aversive withdrawal mechanisms arerelieved, the acute rewarding and acute aversive withdrawaleffects are reinstated.

Although animals with a chronic history of opioid intakeand expressing somatic signs of withdrawal are clearly depen-dent on opioids, we argue that the motivation associated withopioid dependence develops before any of these somatic signsof withdrawal are detected. We suggest that somatic with-

drawal signs are not the best indices of opioid motivation inthe dependent state.

CHALLENGES TO THETWO-MOTIVATIONAL-SYSTEMS HYPOTHESIS

The two-motivational-systems hypothesis rests on the evi-dence that the TPP region subserves the acute rewarding ef-fects of opioids, whereas dopamine is critical for mediatingthe rewarding effects of withdrawal relief by opioids. Thus,when nondependent rats prefer an environment associatedwith morphine rather than a neutral unfamiliar environment,they do so via the TPP-mediated acute reward system. Whendependent and withdrawn rats prefer an opioid-associated en-vironment rather than a neutral unfamiliar one, they do so via

the dopamine-mediated reward system. Because these twomotivational systems are doubly dissociated, one can negatethe possibility that the acute and withdrawal relief rewardingeffects of opioids reflect a quantitative distinction in the inten-sity or degree of reward rather than a qualitative distinctionbetween two different kinds of reward.

Given that our hypothesis rests primarily on place condi-tioning procedures, it is important to rule out some alternateinterpretations of the results. In the behavioral assays of opi-oid withdrawal, opioids are administered to rats in the homecage and saline vehicle in one environment of the place condi-tioning apparatus, and the avoidance of that environment islater assessed. As such, one can argue that the saline-pairedside is most predictive of the absence of opioids. Therefore,

spending less time on that side at testing does not necessarilyreflect a state of aversiveness and avoidance of the saline-(withdrawal) paired side but rather may reflect the avoidanceof stimuli that are exclusively predictive of nonreward (inhibi-tory conditioning). However, several pieces of data speakagainst such a possibility. First, when nondependent rats aregiven a rewarding dose of morphine (2 mg/kg) in the homecage and 21 h later are injected with saline and placed in anenvironment, the rats fail to acquire an avoidance of the sa-line-paired side, which is exclusively predictive of the absenceof reward (5,10). Second, both nondependent and dependentrats can acquire the avoidance of the saline-paired side, butthey do so depending on the time since the last morphine injection during training. That is, 1116 h of morphine absti-nence triggers avoidance in nondependent rats, whereas 1624 h of abstinence triggers avoidance in dependent rats (5). Inboth instances, the saline-paired environment is exclusivelypredictive of the absence of reward. If avoidance of stimulithat predict nonreward is the mechanism underlying thisavoidance behavior, then we should not expect different timeperiods for observing avoidance in nondependent vs. depen-dent rats. Depending on whether animals had an acute history(nondependent) or a chronic history (dependent) of opioid in-take, the avoidance behavior expressed by the rats using ex-actly the same conditioning procedures is blocked by differentneurobiological manipulations (i.e., dopamine antagonistsonly block the avoidance in dependent rats). If rats wereavoiding the withdrawal-paired environment simply becauseit is predictive of nonreward, then it is difficult to explain whydopamine antagonists block one avoidance behavior but notthe other. Therefore, we argue that these aversions reflect twofundamnetally different aversive states of withdrawal associ-ated with opioid dependence and nondependence.

Simple inhibitory conditioning still may explain why non-dependent animals avoid a withdrawal-paired side (58,94).That is, the rats will show conditioned avoidance of an envi-

ronment that predicts a decline in the acute rewarding effectsof a previous morphine injection or endogenous opioid activ-ity and not because of the aversiveness of acute withdrawal.More speculatively, a decrease in endogenous opioid activity(induced by naloxone or by acute withdrawal from a few mor-phine injections) may be the underlying mechanism of inhibi-tory conditioning. However, because TPP lesions do not blockthe aversive conditioning effects of naloxone in nondepen-dent rats (5) (and if the mechanisms of naloxone aversion andacute withdrawal in nondependent animals are the same), wesuggest that inhibitory conditioning is not the mechanism un-derlying the conditioned aversions to acute withdrawal. Nev-ertheless, inhibitory conditioning still can be a possible expla-nation for the avoidance behavior seen in nondependentanimals. However, if TPP lesions do not interfere with the

aversive effects of acute withdrawal seen at 1116 h postmor-phine in nondependent rats, then this data would speak morestrongly against an inhibitory conditioning mechanism.

Given the two-separate-motivational-systems hypothesis,there are several critical issues that can be raised.

Place Conditioning vs. Self-Administration

Given that our two-motivational-systems hypothesis wasderived from place conditioning studies, can this view explainthe results of self-administration studies? TPP lesions inter-fere with the acquisition and initial phase of opioid self-adminis-tration [while animals were likely to be in a nondependent

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state (89)] but not with the maintenance of opioid self-admin-istration after animals become physically dependent (75).However, if dependent animals are allowed to continue toself-adminster opioids for an extended period of time, thenwe predict that the TPP-mediated effects would reemergenear the end of long-duration self-administration sessions.Having said that, it is important to note the difference be-tween a dependent animal with a history of only a few heroininjections vs. one with a chronic history. That is, in the case ofa dependent animal with history of only a few heroin injec-tions, one or two bar presses may be sufficient to alleviatewithdrawal and release the TPP reward system. Accordingly,TPP lesions may interfere with the initial phase of opioid self-administration in animals that have the minimal number ofopioid exposures sufficient to render them dependent on opi-oids (75). In the chronic case, however, it may take manymore bar presses to alleviate withdrawal and for the TPP re-ward system to reemerge.

In contrast to the TPP effects, dopamine antagonists pro-duce the opposite pattern of results. During the acquisitionphase of heroin self-administration, the dopamine antagonisthaloperidol (0.1251.125 mg/kg) has no effect on the reward-ing effects of heroin (i.e., does not increase or decrease therate of bar pressing during the first 2 days of heroin self-adminis-tration) (127). During the maintenance phase of heroin self-administration, the D1 receptor antagonist SCH 23390 sup-presses bar pressing for heroin (below the baseline level) atdoses higher than 0.01 mg/kg and in the absence of catalepsy(81). Ettenberg et al. (27) used 0.01, 0.05, 0.1, 0.2 and 0.4 mg/kg of alpha-flupenthixol to block cocaine or heroin self-ad-ministration. The 0.05-, 0.1- and 0.2-mg/kg doses increased co-caine self-administration. However, 0.2- and 0.4-, but not 0.1-,mg/kg doses decreased heroin self-administration below thesaline injection level. Motoric effects, at least at the 0.2-mg/kgdose, are ruled out because the same dose produced an in-crease in cocaine responding. Thus, two studies with different

dopamine antagonists have shown that dopamine antagonistssuppress heroin self-administration below the baseline level inthe absence of cataleptic effects. It is conventional to assumethat a reduction in reward produces an increase in the rate ofbar pressing, presumably because the animal has to self-administer more to compensate for the reduced reward, butwhat does a dopamine-antagonist-induced decrease in heroinself-administration mean? Does it mean that the dopamineantagonist had no effects on heroin reward, as suggested byEttenberg et al. (27)? Or could it mean that dopamine antago-nists completely blocked the rewarding effects of withdrawalrelief by heroin so that animals were no longer motivated toapproach cues (i.e., the bar) associated with the alleviation ofwithdrawal? We argue that the latter is an equally likely expla-nation.

Another challenging question is why selective lesions of thedopamine terminals in the nucleus accumbens with 6-hydroxy-dopamine (6-OHDA) microinjections (92) did not block themaintenance of heroin self-adminstration. We suggest thatthese results cannot exclude a role for dopamine in opioid re-ward. The nucleus accumbens dopamine is not the onlydopamine link supporting heroin self-administration in thedependent state, and lesioning this dopamine link by itself isnot sufficient to block heroin self-administration. Evidenceexists for other dopamine projections from the midbrain to,e.g., the visceral (agranular insular) cortex, which play a rolein the motivational mechanisms of opioids (139). These alter-nate projections may be sufficient to support the mechanisms

of opioid self-administration in the dependent and withdrawnstate.

Dopamine and Opioid Reward

Previous studies have shown that dopamine antagonistsblock the acquisition of conditioned place preferences toplaces paired with heroin (13,114) or with morphine (107,108).Given the short-term history of exposure to opioids in thesestudies, how do we explain these findings in terms of our pro-posed hypothesis? In an explicit study of this issue using her-oin, Nader et al. (75) demonstrated that just a few injectionsof high doses of heroin, such as those used in the studies ofBozarth and Wise (13) and Spyraki et al. (114), can induce anopioid-dependence state in the absence of any observablesigns of somatic withdrawal. This finding could explain thedopamine-antagonist-induced block of the preferences pro-duced by the very high doses of heroin used in these studies.However, Shippenberg and Herz (107,108) showed thatchronic D1 antagonism with the compound SCH 23390 blocksthe acquisition of a place preference to an environment pairedwith a few low doses of morphine (i.e., a nondependent state).Nevertheless, there are confounding aspects in these results.In control experiments, acute injections of SCH 23390 wereused to assess the motivational effects the antagonist had onits own; in the primary experiments, chronic continuous expo-sure to SCH 23390 delivered by minipumps was used to blockthe conditioned place preferences for morphine (107,108).Most important, even in the control experiments, when theacute dose of SCH 23390 was 100 times lower than the dailyrate of SCH 23390 delivery through the minipumps, the acutedose still produced a robust conditioned place aversion indrug-naive rats (107,108). Thus, when using minipumps with100 times higher doses of SCH 23390, it is quite possible thatthe behavioral aversion produced by SCH 23390 was so greatas to render the pharmacologically intact rewarding effects of

low doses of morphine completely ineffective in supportingplace preferences.Unfortunately, the one place conditioning study that used

acute as opposed to chronic SCH 23390 to challenge the ac-quisition of low-dose morphine place preferences (57) madeuse of a biased place conditioning protocol in which rats wereconsistently conditioned to their least preferred side. Effectsin biased place conditioning procedures are subject to alterna-tive interpretations in terms of stress, anxiety and other non-specific effects (20,125). In a later counterbalanced, unbiasedplace conditioning paradigm, 6-OHDA lesions of (or unilat-eral microinjections of SCH 23390) into the nucleus accum-bens blocked the acquisition of morphine place preferences inpreviously drug-naive rats (106). These findings are surpris-ing, given that the 6-OHDA treatment resulted in only a 46%

depletion of dopamine in the nucleus. Lesions of the mesolim-bic dopaminergic system system that result in 90% dopa-mine depletion often do not cause significant behavioralchanges (95,119). In fact, 6-OHDA lesions of the accumbensthat resulted in approximately 75% decrease in nucleus ac-cumbens dopamine levels had no effect on amphetamineplace preferences (113). It is also suprising that unilateralblockade of dopaminergic receptors in the nucleus accumbenswith SCH 23390 should completely block the acquisition ofsystemic morphine place preferences (106). Rather, if half ofthe rewarding properties produced by systemic morphine areworking through the contralateral nucleus accumbens, thenonly an attenuation of conditioned preferences for the mor-

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phine-paired environments should be seen. At present, it isdifficult to reconcile the cited experiments with our demon-stration that dopamine antagonists (alpha-flupentixol) at apretreatment time that has been shown to have no motiva-tional effects and at a dose that blocks both D1 and D2 recep-tors (104) has no effect on the acquisition of a preference foran environment paired with even a low dose (2 mg/kg intra-peritoneally) of morphine (4).

There remain other questions for which clear answers arenot yet available. First, opioids microinjected into the VTAproduce conditioned place preferences in nondependent ani-mals (21,29,93,124,135). If VTAdopamine neurons do notmediate these preferences, as our hypothesis predicts, thenwhat mediates this acute VTAmorphine reward? We suggestthat the reward signals generated by opioids microinjectedinto the VTA activate nondoapaminergic projections to theTPP in the nondependent state. Evidence shows that the con-ditioned place preferences produced by morphine microin-jected into the VTA in nondependent animals are not blockedby systemic dopamine antagonists but are blocked by TPP le-sions. However, dopamine antagonists block the acquisitionof conditioned preferences for morphine microinjected intothe VTA when animals are in an opioid-dependent and with-drawn state (78,80). Second, opioids microinjected into thenucleus accumbens produce conditioned place preferences innondependent rats (29,124,126). Even so, when animals arechronically exposed to opioids, the microinjection of opioidantagonists into the accumbens produces withdrawal aver-sions (41,55,117). If the neural systems mediating acute re-ward in nondependent animals and the reward of withdrawalrelief in dependent animals are separate, then why is the sameneural region (accumbens) involved in both the acute reward-ing and the aversive withdrawal effects of opioids? Althoughwe do not have experimental evidence to answer this ques-tion, we hypothesize that, similar to the findings with microin-jections into the VTA, the reward signals generated by opi-

oids microinjected into the accumbens activate descendingprojections to the TPP in the nondependent state. However,after chronic exposure to opioids, a separate population ofopiate receptors within the accumbens that are associatedwith dopamine terminals projecting from the VTA becomethe primary substrate mediating the withdrawal motivationaleffects of opioids. Thus, we predict that the conditioned placepreferences produced by opioids microinjected into the ac-cumbens in previously drug-naive animals will be blocked byTPP lesions and not by dopamine antagonists. However, theconditioned place preferences produced by the same microinjections of opioids into the accumbens will be blocked bydopamine antagonists and not by TPP lesions in opiate-depen-dent and withdrawn animals. One may wonder why lesions ofthe TPP region would block the acquisition of opioid place

preference, if the opioid reward signals were generated atmore rostral sites. Our hypothesis implies that the reward sig-nals of opioids in the nondependent state are generated inmultiple rostral regions of the limbic system but that they con-verge to exit the limbic system through the TPP region of thebrainstem.

RELEVANCE TO HUMAN ADDICTION

The two-motivational-systems hypothesis proposes that in-dependent motivational systems mediate the rewarding ef-fects of opioids in the nondependent state and in the physi-cally dependent/withdrawal state. In the opioid-dependent

state and during opioid withdrawal, the rewarding effects ofwithdrawal relief inhibit or mask the acute rewarding effectsinitially exerted in the nondependent state, but the acute re-warding effects are unmasked after the alleviation of with-drawal. Thus, when human drug users are given unlimited ac-cess to drugs, the termination of abstinence can unmask theTPP acute reward system, thus independently leading to a fur-ther escalation in motivation for opioids (8). In the followingsections, we discuss the relevance of this hypothesis to find-ings in human addicts as they relate to systems of reward andaversive withdrawal.

Reward Systems

The two-motivational-systems hypothesis can explain thefindings in human opioid users. As Goldstein (35) describedthe typical history of hard-core addicts, sometimes in adoles-cence, heroin is tried in social setting, at the urging of friends.This usually occurs more out of curiosity and thrill-seekingthan in response to a stressful life situation, although escapefrom stress, anxiety, or intolarable conditions of life can beimportant factors facilitating repeated heroin use in the earlystage. Thus, typical beginning heroin users (with little toler-ance) start by injecting themselves repeatedly, striving to beas high as possible (25). We suggest that this phase of heroin-seeking is analogous to the TPP-mediated acute reward innondependent rats. After repeated heroin use (perhaps a fewdays or a week), the user develops tolerance to the drug, andthe amount of heroin injected becomes insufficient to achievea high (25). At this point, when the user is sick due to with-drawal, he becomes in desperate need for heroin to alleviatewithdrawal (25). The clinical observations indicate that themajority of addicts say that they are currently using heroin toget rid of problems such as withdrawal and stress (35,36,84).These observations are consistent with our view that, whenphysical dependence develops and withdrawal is present, the

TPP system becomes inhibited or masked by the dependencesystem. When withdrawal is alleviated and the heroin user isstabilized on methadone, he becomes protected against with-drawal, which in the past had forced him to seek withdrawalrelief with heroin (24,25). However, once the heroin user is onmethadone and withdrawal is alleviated, the heroin user con-tinues to seek opioids and nonopioid drugs (118), presumablyto achieve a high. This finding is a prediction of our hypothe-sis that once withdrawal is alleviated, the TPP system re-emerges and leads to a further escalation in motivation foropioids. We acknowledge that most heroin users stabilized onmethadone for long periods of time stop completely to useheroin. However, we also point to the fact that in the majorityof cases reported in Canada, addicts do not stay on metha-done for long periods of time, and they go back to their heroin

habit within 6 months after stopping an apparently successfultreatment (90,91).We caution that the neural mechanisms subserving the

subjective sensory experience of highs and euphoria are notsynonymous with the neural systems subserving the motiva-tion to seek drugs. Evidence shows that the sensory discrimi-native effects and the motivational effects of opioids are pro-cessed separately and that one can disrupt one system but notthe other (49,63). However, because the discriminative effectsand motivational effects elicited by opioids always occur atthe same time, they begin to predict one another because oftheir learned association over time (63,76,80). Therefore,when humans seek opioids to get high, we suggest that this

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seeking is due to the sensory cues of the high, which exertpowerful conditioned motivational effects. As long as the sys-tem mediating the subjective effects of the high and the moti-vational system that drives the individual to seek the drug areboth intact, it is difficult to tell the effects of the discrimina-tion and motivation systems apart. However, just as in ani-mals (49,63,97), if the motivational system is selectively dis-rupted, then the high and euphoria still can be experienced,but the conditioned motivational effects of this sensationwould extinguish over time and lose their motivational power.In other words, the addict will no longer be motivated to seekmore drugs. An example that illustrates the dissociation be-tween discriminative sensation and motivation in humansis the administration of morphine to relieve pain in patients.In the absence of morphine, the patient experiences pain, butat the same time the patient is motivated to avoid the sourceof pain. In the presence of morphine, motivation gets dis-rupted, so that the subjective experience of pain can still befelt, but the patient is no longer motivated to do anythingabout it. In this line of reasoning, we assume that the subjec-tive feeling of being high is coactive with the TPP acute re-ward system, whereas the sensory experience of feelingstraight (after withdrawal relief) is coactive with the dopam-ine withdrawal relief system. It is the activation of the motiva-tional systems and not the sensory discrimination systems thatinstigate drug-seeking. However, it is difficult for humans tomake this distinction because (we argue) unconditioned moti-vation itself is not subjectively accessible. Therefore, humansreport that they seek drugs to get high simply because thissubjective sensory experience acquires over time very power-ful conditioned rewarding effects.

Withdrawal Systems

The two-motivational-systems hypothesis is based on theassumption that there are two separate mechanisms for with-

drawal: acute withdrawal observed in the nondependent anddependent states at 1116 h postmorphine in rats and classicwithdrawal observed only in the dependent state at 1624 hpostmorphine in rats. These time frames for detecting with-drawal differ from those observed in humans. For example,time course studies in nondependent human volunteers thatlooked at the naloxone-precipitated effects after a single mor-phine dose found that the most intense subjective withdrawalsymptoms appear at 6 h after morphine administration (52).Hoever, more severe physical signs and subjective symptomsof classic withdrawal in dependent humans were not reporteduntil at least 9 h postmorphine (51). Variations such as dose,schedule of administration, metabolism and species differ-ences may explain why these time frames in the rat model donot match exactly those in humans. However, there is an im-

portant consistency between the two lines of studies in thatthe aversiveness of acute withdrawal appears prior to the se-vere aversiveness of classic withdrawal. The point at whichthe transition from nondependence to dependence occurs isnot known, but studies that have addressed this issue in hu-mans found that there is a time window during which re-peated opioid administrations result in escalation to physicaldependence (53). In other words, if opioid exposures arewidely spaced in time, multiple exposures may have nogreater effects than a single exposure (53). These results sug-gest that opioids can be sought for a long period of timethrough a nondependence motivational system if exposuresare spaced, without necessarily involving a dependence moti-vational system.

It is important to sort out the relationship between thewithdrawal avoidance in rats and the physical signs and subjective symptoms of discomfort reported by humans duringwithdrawal. In a previous section, we argued that the physicalsigns of withdrawal are not synonymous with the aversivenessof withdrawal. Although we mentioned previously that cloni-dine may not be a useful tool in drawing a distinction betweensomatic signs and avoidance of withdrawal in experimentalanimals (because it blocks both phenomena), human studieshave found that clonidine exerts differential effects on the ob-jective autonomic and physical signs vs. the subjective reportof discomfort from morphine withdrawal (31,51). Together,the animal and human findings help illustrate one main point,that the mechanisms underlying the physical signs of with-drawal and the aversiveness of withdrawal are not the samembut the remaining question is whether the subjective symp-toms of morphine withdrawal in humans and the motivationto avoid withdrawal or seek relief are synonymous. So far, wehave not obtained any evidence in experimental animals thataddresses this question directly. However, from what isknown about the neural mechanisms subserving the discrimi-native and rewarding effects of opioids, we hypothesize thatan analogous scenario applies to the discriminative and aver-sive effects of opioid withdrawal. In other words, the subjec-tive sensory experiences of pain and discomfort from with-drawal acquire a motivational power only through associationwith patterned motivational activity in the dopaminergic with-drawal system. Thus, the addict is seen as motivated to avoidthe pain and discomfort of withdrawal or has a great desire toseek relief. We suggest that this motivation is only becausethese two subjective experiences of withdrawal aversivenessand withdrawal relief are associated with changes in activity inthe dopaminergic motivational system. If this dopaminergicmotivational system is interrupted, then the subjective pain ofwithdrawal or the feeling of withdrawal relief may still bepresent, but the addict will no longer be motivated to avoid

withdrawal or seek relief.Unlike the aversive withdrawal and reward systems in thedpendent state that, we suggest, involve the same neural sub-strate (dopamine), the two-motivational-systems hypothesisproposes that the systems mediating acute withdrawal andacute reward in the nondependent state are separate. Al-though indirect evidence suggests that acute withdrawal is notnecessary for opioid-seeking [i.e., lesions of the arcuate nu-cleus do not block morphine conditioned place preference innondependent rats (72)], we still do not know whether acutewithdrawal is sufficient for opioid-seeking. Thus, the subjec-tive experience of disphoria reported by nondependent hu-mans in acute withdrawal may still come to serve as learnedconditioned sensory cues sufficient for driving an individual toseek opioids. However, this sensory experience is not neces-

sary for nor is it related to the neurobiological mechanisms bywhich humans seek opioids for highs and acute rewarding ef-fects.

An important question arising from our two-motivational-systems hypothesis is that, as dopamine antagonists block therewarding effects of opioids in the dependent and withdrawnstate, why do schizophrenic opioid addicts on neurolepticscontinue to self-administer heroin? We argue that neurolep-tics interfere only with the reward process associated with thealleviation of withdrawal. In other words, neuroleptics willblock the motivation to seek relief only if schizophrenics werein a state of severe withdrawal. Although we cannot be pre-cise, we assume that many of these schizophrenic addicts arenot in a state of withdrawal, perhaps because they are nonde-

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pendent, they were detoxified before hospitalization or theyare maintained on opioid medication to control withdrawal.As such, our hypothesis predicts that once withdrawal is alle-viated, the TPP acute reward system reemerges and leads toan escalation in opioid-seeking. Thus, in schizophrenic opioidaddicts, we predict that neuroleptics may render the addictless motivated to seek withdrawal relief only if he were in astate of withdrawal. Otherwise, the acute rewarding effects ofheroin are unmasked, and schizophrenics will seek heroin forits acute rewarding effects, despite the neuroleptic blockade.We also note that indirect evidence from animal studies (65)suggests that neuroleptics may not block the conditioned re-warding effects of withdrawal relief but rather the uncondi-tioned rewarding effects. This suggestion means that, even ifsome schizophrenics were in a state of withdrawal, neurolep-tics will not initially block the motivation for opioids com-pletely. Some conditioned approach to opioids may persistuntil extinction in the schizophrenics. If the amount of opioidstaken during the time before extinction is enough to alleviatewithdrawal and switch to the nondependent state, then wepredict that the TPP system becomes active again and thusdrives the schizophrenics to seek more opioids, despite theneuroleptic medication.

CRITIQUE OF PREVIOUS VIEWS OF ADDICTION

Although several interesting views of addiction have beenpresented over recent years (54,97,116,135), the two oppositepositions presented by Koob and Bloom (54) and Wise andBozarth (135) serve to summarize the divisions in the field re-garding the primary mechanisms responsible for instigatingdrug use. The view proposed by Koob and Bloom (54) is anopponent process (withdrawal/dependence) theory of addic-tion. Opponent process theory supposes that the nervous sys-tem is organized such that rewarding drug stimuli activate re-warding processes that are opposed by aversive processes in a

simple dynamic control system (54,112). Activation of the re-ward processes is hypothesized to follow the drug injectionclosely. In contrast, the opponent aversive processes are hy-pothesized to build up in strength slowly as a function of re-peated exposures to the drug and to decay slowly. Thus, in thepresence of the drug, these aversive processes have relativelyweak effects. After repeated drug exposure (but in the ab-sence of the drug), these opposing aversive processes becomestronger. Koob and Bloom (54) postulated that the aversiveeffects of drug withdrawal eventually become the prime insti-gators of drug motivation because of the need to alleviate thewithdrawal resultant from previous drug use.

The view of Wise and Bozarth (135) is an incentive (psy-chomotor stimulant) based theory of addiction. This theorystresses that drug similar states rather than drug opponent or

withdrawal states as the most powerful stimuli for drug use[drug use can occur through activation of the mesolimbicdopamine system, independent of the presence of any condi-tion of withdrawal (135)]. Chronic opioid use can lead to awithdrawal syndrome. However, withdrawal only accentuates(116) or sensitizes (97) the initial incentive effects producedby opioids (135).

At the level of behavioral description, the place condition-ing data support a withdrawal/opponent process model of mo-tivation. An opioid reward effect and an aversive (presumablyopponent) withdrawal effect were seen in both opioid-nonde-pendent and opioid-dependent animals (4,5). However, at theprocess (i.e., incentive vs. opponent process) and the neural(i.e., dopamine vs. TPP) levels of analysis, the data are incon-

sistent with both the incentive and opponent process views.Several lines of evidence are inconsistent with the opponentprocess explanation of opioid motivation. In the opponentprocess view proposed by Koob and Bloom (54), two possibleneurobiological mechanisms could support the opponent pro-cess. The first is a within-system opponent process in whichthe primary cellular mechanism activated by the drug itselfbecomes tolerant, thus allowing the opponent aversive pro-cess (within the same neural system) to be expressed whenunopposed by the drug. The second is a between-systems op-ponent process in which the initial reward process causes acti-vation of a separate neural system underlying the opponentaversive process (54). Pivotal to all theories of opponent pro-cess is the proposition that the aversive processes are trig-gered by (and thereby completely reliant on) the presence ofan initial reward process. Thus, in the absence of the initial re-ward process, there could be no secondary opponent or aver-sive process. However, TPP lesions that blocked the initialacute rewarding effects of morphine in nondependent rats didnot interfere with the normal development of aversive with-drawal processes (hypothesized to be opponent and depen-dent on the primary rewarding process), such as the with-drawal aversions seen in dependent rats and the naloxoneaversions (or spontaneous withdrawal aversions from acutemorphine injections) observed in nondependent rats (5,10).These findings are inconsistent with the core assumption ofopponent theories of drug-seeking behavior because themechanisms mediating the induction of dependence and with-drawal are independent of the mechanisms mediating acutereward. Second, although the aversiveness of withdrawal maybe critical for opioid motivation in opioid-dependent rats [be-cause dopamine antagonists block the aversiveness of with-drawal and the rewarding effects of withdrawal relief by mor-phine (4)], a similar withdrawal phenomenon [i.e., naloxoneor acute withdrawal after a few morphine injections (5)] innondependent rats is not necessary (although it might be suf-

ficient) for the rewarding effects of morphine [because arcu-ate nucleus lesions block the aversive effects of naloxonewithout interfering with the acute rewarding properties ofmorphine in nondependent rats (72)]. Third, although bothreward and withdrawal effects are observed in nondependentand dependent animals (5,8), these reward/withdrawal pro-cesses in the nondependent vs. the dependent states dependon different neural substrates (5), thus questioning the notionthat the same neural circuit mediating initial drug reward(acute reward) comes to serve as the substrate for withdrawalalleviation in the dependent state (54).

Several lines of evidence also are inconsistent with the in-centive/psychostimulant view of opioid motivation. First, twoindependent mechanisms mediate the incentive effects of opi-oids in nondependent (TPP) and opioid-dependent (dopa-

mine) animals (4). Moreover, our data suggest that only oneof these processes is dominant at any one time. Although theincentive/psychostimulant view acknowledges the existence ofseparate reward (positive reinforcement) and withdrawal-relief (negative reinforcement) mechanisms, this theory positsthat both mechanisms are concurrently active. We suggestthat this discrepancy between models is due to the fact thatthe incentive/psychostimulant model defines withdrawal interms of somatic withdrawal signs, which are separate fromthe aversive effects of withdrawal. Second, withdrawal doesnot result in sensitization of the acute incentive effects (TPP)of opioids. On the contrary, withdrawal prevents the expres-sion of these TPP-mediated incentive effects (8). Third, thefindings that all of the rewarding effects of morphine in de-

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pendent and withdrawn rats are due to withdrawal relief(4,79) question the premises of the incentive/psychomotorstimulant views of addiction by stressing that withdrawal isnot important for drug reward and that drug-similar (ratherthan withdrawal or drug-opponent) states can account for allinstances of drug-seeking.

At the neural level, proponents of the incentive and thewithdrawal/opponent process views ascribe a critical role forthe dopaminergic VTA projection to the nucleus accumbensin the rewarding effects of psychoactive drugs (54,97,116,135).In turn, it has been proposed that the nucleus accumbens actsas a limbic-motor integrator that converts reward into action(68) and that, through reciprocal interactions with theamygdala, stimulus-reward associations are formed (18,28,47).One main difference, however, is that the incentive view as-serts that the dopaminergic projection to the accumbens iscritical for opioid and stimulant (cocaine/amphetamine) re-wards, whereas opponent process proponents (54) suggest acritical role for dopaminergic projections in stimulant rewardand for the nondopaminergic projection from the accumbensto the ventral pallidum in opioid reward. However, this oppo-nent process view does not explain why excitatory amino acidlesions of the nucleus accumbens do not block the condi-tioned place preferences produced by morphine in nondepen-dent animals (85,87), nor does it explain why dopamine antag-onists block opioid reward selectively in dependent animals(4). Similarly, the psychostimulant view does not explain whydopamine antagonists has no effect on the rewarding effectsof heroin during the initial acquisition of heroin self-adminis-tration (127), nor it does explain why the blockade of dopa-mine function does not block morphine-conditioned placepreference in nondependent animals (4,75). Thus, a singleVTAaccumbenspallidal circuitry cannot accommodate thefindings that opioids elicit rewarding effects through activa-tion of two mechanisms in the brain: one through the TPPsubserving the acute rewarding effects of opioids in the non-

dependent state and a separate dopamine-mediated circuitrysubserving the rewarding effects of withdrawal relief by opi-oids in the dependent state.

IMPLICATIONS FOR THE DEVELOPMENT OF POSSIBLEPHARMACOTHERAPIES FOR OPIOID ADDICTION

One of the hopes from studies of the neurobiological basesof opioid addiction is the rational outline of pharmacothera-peutic strategies for breaking the cycle of addiction. From theopponent process view of addiction, one infers that the mosteffective strategy would be the interference with the oppo-nent (withdrawal) process. Conversely, from the incentiveview, one infers that the best strategy would be the interfer-ence with the process that mediates acute reward. Obviously,

our position is that both withdrawal and acute reward pro-cesses must be interrupted to block opioid-seeking. Our datasuggest that dopamine antagonists interfere with the with-drawal and withdrawal-relief processes of the dependence sys-tem. So far, our studies have not addressed the issue of interfer-ing with acute withdrawal. In the following paragraphs, wediscuss potential strategies for interfering with acute reward.

Interestingly, a recent study has uncovered two separatemechanisms for cocaine-seeking (105) that are reminiscent ofthe two-opioid motivational mechanisms we propose in thisreview, i.e., a D1-receptor system that provides a sense ofgratification (perhaps analogous to the withdrawal-relief sys-tem) and a D2-receptor system that triggers an escalation indrug-seeking (perhaps analogous to the TPP acute reward

system). Although, our review does not address the neuralsystems involved in cocaine-seeking or how these systems re-late to opioid-seeking, there are conceptual parallels betweenthe two studies that deserve attention. Self et al. (105) sug-gested that a good approach to block drug-seeking behavior isto stimulate the D1-receptor system with agonists, in the hopeof providing gratification in cocaine-dependent humans with-out triggering a drive to seek more cocaine (82). Given theparallel between cocaine and opioids in having a withdrawal-relief-like system and an acute-reward-like system (irrespec-tive of the neural substrates subserving these reward systems),we predict that activation of the withdrawal-relief system willlead to gratification while unmasking the acute reward systemand thus trigger a new drive to seek cocaine.

Thus, in addition to the blockade of the withdrawal-inducedmechanisms of opioid-seeking, it will be necessary to devisepharmacotherapeutic strategies that selectively interfere withthe acute rewarding effects of opioids. However, the questionis which part of the acute reward circuitry should be targetedfor disruption? Drugs that block opioid action, either by pre-venting opioids from binding to the receptor (i.e., antagonists)or perhaps by interfering with the transfer of the opioid signalfrom the receptor to the cell, are problematic for two reasons.First, although this strategy blocks both the dependent andnondependent motivational systems, the opiate addict will notcomply with such a strategy because receptor blockade pre-cipitates a withdrawal syndrome. Second, even if withdrawalwas completely absent, the addict will not comply with an opi-ate-receptor-blockade strategy because the blockade also willblock the discriminative opioid effects (i.e., the high). Al-though experimental evidence reveals that the discriminativeeffects of opioids are separate from their motivational effects(which energize the seeking of opioids), the close associationof discriminative and motivational effects render the sensoryexperience of the high as a very powerful positive cue in opi-oid-seeking. Thus, when an opioid-blocking drug prevents the

experience of a high, the addict will be motivated to avoidsuch a drug and not comply with the therapy. In support ofthis argument is the observation that it is difficult to persuadeheroin addicts to take naltrexone for the control of depen-dence (36,37). Therefore, we suggest that an effective strategywould be to interrupt the acute reward system at a point sev-eral synapses after the opioid-receptor-bearing neurons, i.e.,after the mechanisms mediating the motivational and discrim-inative effects of opioids become separate. The TPP region isan ideal site for making this interruption because lesioning theTPP does not affect the withdrawal mechanisms of opioids,nor does it interfere with the discriminative effects of opioids.As such, we speculate that an addict may comply with taking adrug that blocks neurotransmission in the TPP region becausethe drug will not precipitate any form of withdrawal and

should not interfere with getting high. However, once the TPPis blocked, the conditioned motivational effects of the highwill extinguish over time. Ultimately, the addict can still expe-rience the high from opioids. However, this sensory experi-ence will lose its motivational power through extinction, andthe addict will be no longer motivated to seek more highs andmore opioids.

CONCLUSION

The two-motivational-systems hypothesis for opioids alsomay help explain the motivational effects of nonopioid stimuliin so far as these motivational effects produced by these otherstimuli also obey a boundary between deprivation and non-

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deprivation states (76). Dopamine antagonists block the re-warding effects of food in food-deprived (133,136) but not infood-sated (4) rats. These findings are the mirror image of theTPP lesion results showing a blockade of the rewarding ef-fects of food in sated but not in food-deprived rats (10). Simi-larly, TPP lesions do not interfere with food self-administra-tion during the initial phase of a progressive ratio schedule(96), presumably when animals are still in a state of food dep-rivation. The same lesions, however, strongly interfere withfood self-administration during the later phase of the progres-sive ratio schedule (96), presumably after animals have eatenenough food pellets to alleviate hunger and switch to a non-deprivation state. Robertson et al. (96) provided a learningand memory (rather than a motivational) interpretation for

these data, but their results also are consistent with a two-motivational-system interpretation. Given the similar behav-ioral patterns dependent on deprivation state with both opi-oids and food and the analagous effects of TPP lesions anddopamine antagonists in both the opioid and food motiva-tional systems, the results are consistent with the notion thatopioids may directly activate the neural processes thatevolved to subserve natural motivation (116,133).

ACKNOWLEDGEMENTS

This work was supported by the Medical Research Council ofCanada.

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