Neurobiology of Conditioning to Drugs of Abuse JANE STEWART C e n t w f i Studies in Behaviwcll Neurobwlogy Department of PFhohm, concmdia Univevsity 1455 de M a i s o n m Botrlevad W Montrhl, W b e c , Canada H3G l M 8 INTRODUCTION Conditioning is a form of associative learning about the co-occurrence of two stimulus events. If one stimulus reliably predicts the occurrence of a second, and if each of them can activate some neural elements in common, a change will occur in the ability of the first, the conditional stimulus (CS), to activate processes originally activated only by the second, the unconditioned stimulus (UCS). If the UCS elicits measurable changes in behavior or neural activity, then evidence that the relation between the CS and the UCS has been learned is found in the ability of the CS alone to elicit some of the changes originally produced by the UCS. This phenomenon was originally demonstrated by Pavlov who studied the conditioning of food-elicited salivation and digestive responses to neutral environmental stimuli. UCSs such as food that have motivational significance for an animal elicit a wide variety of responses including autonomic and regulatory responses, consummatory responses and investigatory and approach responses. If the UCS elicits general approach or avoidance, then the CS will come to elicit general approach or avoidance as well. Advantage has been taken of this by those studying the positive motivational properties of drugs of abuse in the paradigm known as the conditioned place preference in which one of two distinctive places is repeatedly paired with a drug injection and the other with saline. On a test for conditioning when no drug is given, an increase in the time that the animal chooses to spend in the place previously paired with the drug injection is taken as a measure of conditioning of affective processes or motivation. The effects of a CS can also be measured by the way it changes the response to the UCS and to other stimuli in the environment. If, for example, the occurrence of a receptive female rat, a motivationally positive stimulus for the male, is signaled by a CS, then the initiation and completion of copulation will occur more quickly.' The CS appears to activate sexual arousal which in turn facilitates the response to the female and the performance of copulation itself. In the context of conditioning to drugs of abuse, I mention these points for two reasons. The first is that drugs of abuse, as do other motivationally important UCS, have many central nervous system actions. Only some of them are related to their abuse potential. CSs repeatedly paired with drugs of abuse gain the power to elicit many of the actions originally elicited by the drugs themselves, so-called conditioned drug effects. I will argue that drug-paired CSs have the potential to alter subsequent drug335
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related behaviors in two ways:by modifying the effects of drugs taken in their presence, and by eliciting conditioned effects that may contribute to relapse to drug-taking in drug-free individuals. In order to understand the contribution ofconditioning to drugrelated behaviors it w ill be important to determine which conditioned effects of drugs actually contribute to their abuse and how CSs gain the ability to control or modify the expression of drug actions.
CONDITIONED DRUG EFFECTS Pavlov* reporting on the experiments of a certain Dr. Krylov of the Tashkent Bacteriological Laboratory wrote: It is well known that the first effect of a hypodermic injection of morphine (in the dog) is to produce nausea with profuse secretion of saliva, tbllowed by vomiting, and then rotbund sleep. Dr. Krylov, however, observed when the injections were repeate regularly that after 5 or 6 days the preliminaries of injection were in themselves sufficient to produce all these sym toms-nausea, secretion of saliva, vomiting and sleep. Under these circumstancese!t symptoms are now the effect, not of the morphine acting through the blood stream directly on the vomitinB centre, but of all the external stimuli which previously had preceded the injection of morphine . . .
s
Pavlov continued,
. . . in the most striking cases all the symptoms could be produced by the dog simply seeing the experimenter. Where such a stimulus was insufficient it was necessary to open the box containing the syringe, to crop the fur over a small area of skin and wipe with alcohol, and erhaps even to inject some harmless fluid before the symptoms could be obtained: In the years since these observations were made, conditioned drug effects have been demonstrated to a wide range of centrally acting drugs and the potential importance of such effects for an understanding of the long-lasting consequences of drug use has been raised by numerous investigators.3" But although we continue to give lipservice to this view, little has been done to truly advance our understanding of these matters. There are steady advances in knowledge of the mechanisms of actions of various drugs of abuse; we are beginning to identify which actions of drugs are related to their abuse potential; and yet almost nothing is known about the mechanisms underlying the conditioning of these actions of drugs and how conditioned stimuli act to influence drug-taking behavior. What we lack are neural models to help us think about ways in which conditioned environmental stimuli can come to elicit drug effects or to modify the actions of drugs themselves.
If conalit3mring Lr to ocnc* to the E&s
of-s, Gmditbd Stimnli Must Haw Acuss to the Ccncral Neunal Ehaents Utublyhy Those E p t t S
Drugs may have effects on several response systems both within the central nervous system (CNS) and in the periphery. Some of the observed effects of drugs are produced directly by their action on central nervous system elements, whereas others are pmduced by their actions in the periphery. It is often found that drugs produce opposing changes depending on the time after injection and the dose administered. A high dose of morphine, for example, may produce hypothermia fbllowed by hyperthermia. It is
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important when trying to think about conditioned drug effects to realize that such biphasic effects could arise either from the output of two independent CNS systems, each directly activated by a drug, or from the output of a single CNS system responding to compensate fbr the initial drug action. The nature and direction of a conditioned drug effect, or conditioned response (CR), therefore, will not be easily predicted from the observed drug effects, but will depend on our knowledge of which CNS response systems are actually activated. If, as stated above, conditioning of a drug effect depends on the access of the neural elements excited by the CS to those CNS elements activated either directly or indirectly by the drug, it will be necessary to know how the drug effects are produced. Some conditioned drug effects will mimic the observed drug effect (so-called drug-like CRs) whereas others will oppose the observed drug effect (socalled drug-opposite CRs). In a recent issue of TIPS, B. Max,' though apparently interested in such effects, remarked scornfully that the problem with people working in the field is that they wanted to eat their cake and have it too; in other words, we wanted our conditioned drug effects both ways. We don't want them both ways, they are both ways, just as drug effects often are!
In studies of conditioned drug effects in animals, it has become standard to include at least three groups: a group which during the conditioning phase receives the drug on several occasions in the presence of a distinctive set of environmental stimuli (CSs) and saline in the absence of these stimuli (a PAIRED group), a group that receives saline in the presence of the distinctive stimuli and the drug injection in their absence (an UNPAIRED group), and a group that receives saline in both conditions (a CONTROL group). In a standard test for conditioning, all groups are presented with the CS in the absence of drug and the responses to the CS are compared. In a test for CS control of drug actions, all groups are given the drug in the presence of the CS and effects of the drug are compared. CS may act to diminish or to enhance the effect of a drug; the former can be referred to as the CS control of tolerance and the latter the CS control of sensitization.
CONDITIONING AND THE BEHAVIORAL ACTIVATING EPPECIS OF STIMULANT AND OPIOID DRUGS Common Nncral E h t s Undrrlic Somc of tbc Bebapimal Actions of
Stimulant and opioia L h g s Systemic injections of either amphetamine or cocaine lead to increased behavioral activation, locomotor activity and at higher doses to stereotypy, which with repeated injections shows sensitization.8 These effects are mediated by actions on the mesolimbic and striatal dopamine (DA) neurons where amphetamine increases extracellular DA by direct release and reuptake blockade, and cocaine by reuptake blockade. Acute systemic injections of medium to high doses of morphine produce in rats depressant effects fbllowed by excitatory effects. These are seen in the initial motor depression fbllowed by heightened locomotor activity. With repeated intermittent injec-
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tion the depressant actions show rapid tolerance revealing only the excitatory effects. The locomotor-activating effects of morphine can be elicited independently of the depressant actions, as shown by the direct application of morphine to the cell body regions of the mesolimbic and striatal dopamine (DA) neurons. Here morphine and other opioids act to increase firing in DA neurons thereby increasing extracellular dopamine in both cell body and terminal regions. As has been discussed in previous papers presented at this meeting, repeated injections of opioids lead, as do those of amphetamine and cocaine, to sensitization of the behavioral activating effects which appears to be mediated by long-term functional changes in the midbrain DA neuron^.^ When systemic injections of drugs h m either class are repeatedly paired with a set of environmental stimuli (CSs), increased locomotor activity is seen in the presence of these CSs when they are presented alone, that is, behavioral activation is elicited by the CSs. When repeated exposure to these drugs is paired exclusively with a set of environmental stimuli, the behavioral sensitization to the drugs is manifested only in the presence of these stimuli, that is, the expression of sensitization comes under CS control. 10 This set of findings should be of particular interest to those interested in the motivational effects of stimulant and opioid drugs and to the long-term consequences of their use. The mesolimbic DA system appears to be a behavioral ficilitatory system. Activity in this system promotes forward locomotion, enhances the behavioral effectiveness of positive incentive stimuli, and appears to underlie the motivational or rewarding properties of stimulant and opioid drugs as well as those of more natural positive incentives. l1 Sensitized hnctioning within this system could serve to enhance the response to stimuli having neural access to it. The fict that CSs are able to modulate the behavioral sensitization to drugs and to elicit drug-like behavioral activation in the absence of drugs implies that CSs may p n access directly to the facilitation system itself, i.e., the mesolimbic DA system, o r to those response systems activated by it, o r to both. These possibilities are shown in the diagram in FIGURE1. This diagram shows stimuli serving as CSs to have weak, but direct access to the ficilitation system. There is evidence for this from studies of responses of DA neurons to novel sensory stimuli. 12-15 Though these effects would normally habituate with repeated presenta-
cs
1
cs
2
RESPONSE
ucs
PIGURE 1. Diagram showing possible ways in which a conditional stimulus (CS)could gain access to neural units activated by an unconditioned stimulus (UCS). CSs neurons are shown to have weak, but direct access to a behavioral facilitation system normally activated by the UCS. The CSs are also shown to have access to some response units normally activated by the UCS via the facilitator. Changes in the behavioral effectiveness of a CS could be mediated by neural changes at either site through the co-occurrence of the CS and UCS (see text).
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tion, when a CS is paired with a UCS that activates the facilitator, the ability of the CS to activate the facilitator is strengthened or reinforced. In addition, the CS are shown to have access to certain response units normally activated by the UCS via the facilitator. Through repeated paired presentations of the CS and UCS, the capability of the CS to activate these responses would be strengthened by co-occurrence of activity in the CS neurons and the facilitator neurons. Either one or both of these mechanisms could underlie the conditioning of behavioral activation produced by the effects of drugs on the facilitator. Whether either or both of these effects underlies conditioned effects produced by a particular drug should depend on how that drug interacts with the DA facilitatory system to produce its unconditioned behavioral activational effect. Increased extracellular DA from midbrain DA neurons is common to the actions of morphine, amphetamine and cocaine. Increased extracellular DA at terminals is responsible for the behavioral activation produced by amphetamine and cocaine and, at least in part, for that produced by morphine; increased extracellular DA in the cell body region, appears to initiate processes responsible for the development of sensitization to these drugs, but we have not as yet identified the role of DA in conditioned activity to these drugs or in the CS control of the expression of behavioral sensitization to these drugs. As we explore what is known about conditioned effects, it is important to keep in mind how increased extracellular DA levels are achieved in the case of each drug. Morphine acts to increase DA cell firing causing impulse-dependent release. Cocaine interferes with the reuptake of DA, but release depends on impulses initiated by other means. In both cases the opportunity for concurrent activity in CS neurons and the DA neurons would exist making it possible that CS could come to activate DA neurons directly. The situation is less clear, however, for amphetamine which causes release directly, independent of firing in the DA neuron. In all three cases the possibility for CS-UCS interactions exist in the terminal regions of the DA neurons, either pre- or post-synaptically.
The locomotor activity elicited and the sensitization that develops when morphine is applied directly into the ventral t e p e n t a l area (VTA) can be brought under CS control. We showed that animals given pairings of the distinctive environment of an activity box and intra-VlX morphine (PAIRED) were more active in that environment compared to animals that received the same morphine injections elsewhere (UNPAIRED), or no morphine in either environment (CONTROL), when placed in it following placebo injections. Moreover, on a test for sensitization when d animals received intra-VTA morphine, only group PAIRED showed sensitization to the effects of morphine.16 Thus it appeared that repeated activation of the mesolimbic DA system in the presence of a specific set of environmental stimuli was a sufficient condition for the development of drug-induced conditioned activity and conditioned control of the expression of sensitized responding to intra-VTA morphine. We later showed that animals preexposed to systemic injections of amphetamine in the activity boxes were significantly more active in this environment on tests for cross-sensitization to morphine given either systemically or intra-VTA than were animals in either an UNPAIRED or CONTROL group. 17
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In an attempt to specify where the effects of the CS might interact with the unconditioned effects of these drugs to allow for conditioned activity and CS control of sensitization, we studied the development of sensitization to the effects of amphetamine injected directly into the VTA or the nucleus accumbens (NAC) using a conditioning paradigm.l8 Sensitization developed following repeated VTA amphetamine injections, as reported previously,19but there was no evidence for conditioned activity or for CS control of the expression of sensitization; sensitization did not develop following repeated NAC injections19JO nor was there evidence for conditioning. In this case, DA release and reuptake blockade from the somatodendritic region of the neurons, though sufficient for the development of sensitization, appeared not to engage the neural circuitry in a manner that allowed the integration of sensory information necessary for the development of CS control. In addition, excessive post-synaptic DA receptor stimulation in the NAC alone, led neither to conditioning of activity nor sensitization even though the animals were very active during drug exposure. These experiments are summarized in TABLE 1. It can be seen that only when DA neurons are activated to release DA from both somatodendritic regions and from their terminals allowing for feedback from postsynaptic regions can the interaction between sensory and drug-produced signals occur that is necessary for CSs to gun control of behavior. What we do not know is whether the CSs paired with these types of drug actions gain access, either directly or indirectly, to the DA cells. There is the possibility that the activity seen when the CS is presented alone or with drug is due to CS modification of activity in DA neurons per re, to learned modifications in circuits no longer DAdependent, or to both. There are several studies of the effects of DA antagonists on the CS control of sensitization and on conditioned activity that have tried to address this question. Pimozide, a non-selective antagonist, has been reported to block the development of conditioned activity based on amphetamine or cocaine, but not to block its expression; the effects on CS control of sensitization were not tested in these experiments.ZlJ2 In another experiment, however, conditioned circling based on amphetamine was found to be attenuated by both SCH-23390 and the D2 blocker metoclopramide.23 Weiss et aLZ4reported that haloperidol blocked the development, but not the expression of sensitization to cocaine, both of which were CS-dependent. Gold etal.25 showed that the expression of conditioned activity to amphetamine was blocked by 6-hydroxydopamine (6-OHDA) lesions of the mesolimbic DA system. These results suggest that DA neuron activity can be involved in both the development and expression of con-
TABLE 1. Summary of Data from Sensitization Experiments Using Systemic and Intracranial Injections of Amphetamine and Morphine Conditioned
DA Release Preexposure Drug Amphetamine i.p. Amphetamine VTA Amphetamine NAC Morphine i.p. Morphine VTA Morphine NAC
Cell Body
Terminal
+ +
+
-
+ +
Animal Active
Behavioral Sensitization
+
+ +
-
-
+ + +
+ + + +
Non-DA-dependent
+
+
-
Stimulus Control
+
-
+ + ?
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ditioned activity based on stimulant drug such as amphetamine and cocaine, but that under some conditions the conditioned activity can be DA-independent. Interestingly, the findings with the direct agonist, apomorphine, suggest that the conditioned response is DA-independent. It has been shown that in the unilaterally 6-OHDAlesioned rat, the direct DA receptor agonist, apomorphine, produces strong conditioned contralateral turning which was not blocked by haloperid01.M.~~ It is not clear from these studies, however, how apomorphine has its effects on turning in the unilaterally 6-OHDA-lesioned animal. It is possible that the remaining intact contralateral DA system or residual fibers on the lesioned side are involved. The hct that the unconditioned and the conditioned effects were obtained with .05 mgkg apomorphine, an autoreceptor selective dose, which could increase contralateral turning by inhibiting firing and DA release on the non-lesioned side, and that the conditioned effects were most obvious six weeks post su’gery, at a time when compensatory changes in remaining fibers would have occurred, supports this idea. There is a growing literature on conditioning and sensitization in normal animals with direct DA agonists including the mixed Dl/D2 agonist, apom0rphine.2~J~Mattingly30 has shown recently that sensitization to apomorphine, as has previously been shown for amphetamine23.31.32 is blocked by the D1 antagonist, SCH-23390, but not by a selective D2 antagonist. The D2 selective agonist, bromocriptine33 also leads to sensitization that is completely under CS control and is not blocked by the DI antagonist. It appears that sensitization and conditioning induced by these direct acting drugs may be mediated differently from each other and from that fbund with the indirectly acting stimulants. For example, there is no cross-sensitization between bromocriptine and cocaine or heroin.” Although considerable work will be required for an understanding of the bases of these differences, it does appear that there are conditioned changes that are dependent on the DA system fbr their expression and others that are not. It may be that CSs gain access to circuits involved in the activation of DA neurons at the somatodendritic region or in the release of DA directly from terminals, and to circuits that are modulated by DA during learning, but that once modified are DA-independent. Conditioned behavioral hcilitation produced by CSpairings with drugs such as morphine, amphetamine, and cocaine probably involve both types of circuits: The situation may be different in the case of direct DA agonists which do not cause DA release either directly or indirectly.
It has been reported35 that systemic injections of the noncompetitive N-methyl+ aspartate (NMDA) receptor antagonist, MK801, block the development of sensitization to both amphetamine and cocaine implicating the actions of excitatory amino acids (EAA) at NMDA receptors in the plastic changes brought about by repeated drug administration. Because of the known role of NMDA receptors in several instances of learning, we considered that MK801 might be acting by blocking conditioning of behavioral activation rather than the development of sensitization pc’ sc. Using the two sets of the usual three groups, PAIRED, UNPAIRED and CONTROL, one pretreated with MK801 and the other with saline during the conditioning phase, we showed that in the MK801-pretreated groups there was no evidence for conditioned activity on the test fbr Conditioning, nor was there any evidence fbr sensitization when
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these animals were tested with amphetamine alone.% We can say h m this experiment that MK801 blocked the development of conditioned activity, however, we cannot determine whether sensitization was blocked independently from conditioning, or whether MK801 interfered with the effectivenessofamphetamine as a UCS (but see ref. 37). In order to do this, a sensitization paradigm that does not allow for the possibility of conditioned effects must be used. Experiments are currently under way in our laboratory to explore this question. The idea, however, that MK801 interferes with conditioning of the drug effect is supported by the results of a recently reported experiment38 in which it was fbund, using a morphine treatment regimen known to produce environment-specific analgesic tolerance,39that MK801 blocked the development of tolerance to the analgesic effects of morphine, without affecting analgesia pw re.
A ROLE FOR CONDITIONED DRUG EFFECTS IN DRUG-TAKING It has long been proposed that conditioned drug effects play a role in relapse to drug-taking in experienced, drug-free individuals. Two kinds of conditioned effects have been proposed to play such a role: drug-opposite effects or those associated with withdrawal, and drug-like effects. Drug-opposite conditioned effects are said to precipitate drug-taking by creating aversive symptoms resembling withdrawal,3*6whereas drug-like effects are said to create a positive motivational state, enhancing the incentive value of drug-related stimuli, and thereby increasing the probability of drug-related thoughts and action^.^ Both types of conditioned effects have been shown to occur. However, studies done in animals in search of evidence that conditioned aversive effects lead to drug-taking have been unsuccesshl (see ref. 5 for a review and ref. 39). On the other hand, numerous studies have shown that animals seek out places associated with drugs and respond persistently to stimuli associated with them. Conditioning of the unconditioned reinforcing and behavioral activating effects of opioid and stimulant drugs occurs readily. These unconditioned drug effects are mediated at least in part by the mesolimbic DA system and that activity in this system is increased by natural incentives and in turn enhances the effectivenessof incentive stimuli. These observations taken together lead logically to the hypothesis that CSs associated with these drugs might increase activity in this system and thus serve to increase the probability of drug-taking behaviors.
c m t a i k d Drug E F s in Witbdnzwal and *a
Abstinence
In an early study of the conditioned effects of opioids, it was shown in rats that presentation of a CS that had been paired repeatedly with morphine could reverse the decrease in body temperature that accompanies withdrawal from morphine.41 Animals were maintained on high doses of morphine and then the drug was abruptly withdrawn. Core temperature was measured every 12 hours over three subsequent days. Presentation of the bell CS was able to reverne the withdrawal precipitated hypothermia. In a subsequent study the conditioning of body temperature changes produced by morphine was observed both during the period of repeated daily morphine injections and after a period of a b ~ t i n e n c eGroups .~~ of animals were given injections of either 0, 5, 25, or escalating to 100 mg/kg morphine i.p. The daily routine was to
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measure temperature at 09:OOh in the home cage (HC), to transport the animals to a distinctive preinjection environment (PreINJ) at 10:00h, to measure their temperature there at ll:OOh, to transport them to a distinctively different injection environment (INJ) at 12:OOh and to give the daily injection immediately. Temperature was measured at 12:45 and at 14:15h in the injection environment. During the conditioning phase, animals in the morphine treatment groups were hypothermic at 11:OOh in PreINJ compared to control group animals and compared to themselves at 11:OOh in the HC. This effect, seen 23 hours after the previous morphine injection, suggested a withdrawal-like hypothermia which was subsequently shown to be precipitated by the time of day and to be exaggerated by the PreINJ mom cues. Following a period of abstinence, this preINJ hypothermia was n o longer evident, but when animals were placed in INJ and given saline, body temperature rose and marked hyperthermia relative to control group animals was seen at 12:45h and 14:15h. This experiment demonstrates that CSs previously paired with morphine injections caused conditioned hyperthermia (an excitatory drug-like CR) in drug-free animals after a prolonged period of abstinence. A very similar pattern of results was obtained when amphetamine was used as the drug for conditioning43 An interesting parallel to these findings was found in a recent study o n conditioned heart rate changes to ethanol.44 Volunteer social drinkers were given discriminative conditioning to ethanol using a combination of a distinctive room and a flavored drink as Css. During the period of conditioning, subjects were brought into one of the rooms and then given a flavored drink containing ethanol; in the other room a different flavored drink contained no ethanol. Heart rate rose in response to ethanol and remained higher than that of control subjects over the 30 minute test period. O n the tests for conditioning, subjects were presented with each of the CSs alone or in combination. Presentation of the Room alone led to a decrease in heart rate from baseline. Presentation of the Flavored Drink (in a neutral room) led to a sharp increase in heart rate; the combination of cues Room then Drink led to changes that were similar to the Room alone. This study points out that not only can opposite conditioned responses be obtained, but that different elements of the stimulus complex may lead to different conditioned responses. In this case the stimulus most proximal to and that best predicted the ethanol led to a response that mimicked the unconditioned effect of the drug. It would have been interesting to see what would have happened to the two responses as the time between the original conditioning trials and the tests increased.
Repeated presentation of a CS in the absence of the unconditioned stimulus leads to the reduction and elimination of the CR. This phenomenon, known as extinction,
has been the basis of various therapies aimed at eliminating conditioned drug effects;45the assumption being that conditioned drug effects play a role in drug-taking and in relapse to drug-taking after abstinence. CRs are known to be resistant to change and are not eliminated without extinction training. Furthermore, extinction is a fragile process and does not erase the original learning. Extinguished responses are found to recover “spontaneously” with the passage of time and to be easily reinstated by a single CS-UCS pairing. Bouton& has shown in a series of experiments that extinction makes behavior especially sensitive to the background or context in which extinction
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occurs. A response may appear to be eliminated by extinction trials in one context, only to be fully reinstated in another. Contextual cues as diverse as physical environments, drug states and emotions can reinstate the ability of CSs to elicit CRs. In our studies of the CS control of the expression of sensitization of the locomotor effects of am~hetarnine4~ and m0rphine,4~we studied the effects of extinction training o n previously established CS control of sensitization. The three standard groups were used in each experiment (groups PAIRED, UNPAIRED, and CONTROL). Conditioned activity and CS control of sensitization were both evident o n tests made following CS drug pairings. A series of extinction sessions followed during which all groups were tested repeatedly in the activity boxes, but after being given saline injections only both in the activity boxes and in the home cages. By the last day of extinction there were n o differences in activity between groups, it-., n o evidence of conditioning. O n the tests for sensitization which followed, however, in which all animals were given drug before going into the activity boxes, sensitized responding was reinstated. In the case of morphine, animals in group PAIRED were once again significantly more active than animals in the other two groups. Interestingly in the case ofamphetamine, both group PAIRED and UNPAIRED were now more active than CONTROL, suggesting that the extinction sessions had eliminated the inhibition of the expression of sensitization previously seen in group UNPAIRED when tested in the CS-environment. These findings are reminiscent of those from experiments o n reinstatement of drug self-administration. In these experiments it is found that, following a period of extinction in which responding is n o longer reinforced, noncontingent injections of the drug reinstate drug-taking behavior, suggesting that the drug reinstates the effectiveness of drug-related stimuli, or CSs.49-52 These findings show that, in spite of extensive extinction experience in which conditioned stimuli are repeatedly presented in the absence of drug, the effectiveness of such stimuli is easily reinstated by simple re-exposure to the drug in their presence. There is also good reason to think that exposure to other similarly acting drugs and to stresson, both of which show cross-sensitization (see ref. 53), and the arousal of strong positive emotions could all act to reinstate the effectiveness of these stimuli.
REFERENCES 1 . ZAMBLE, E., G. M. HADAD, J . B. MITCHELL& T. R H. CUTMORE. 1985. Pavlovian conditioning of sexual arousal: First- and second-order effects. J. Exp. Psychol. (Anim. Behav.) 11: 598-610. 2. PAVLOV, I. P. 1926. Conditioned reflexes. Dover Press. New York. 3. SIEGEL, S . 1977. Learning and psychopharmacology. In Psychopharmacologyin the Practice of Medicine. M. E. Jarvik, Ed.: 59-70. Appleton-Century-Crofts.New York. 4. SOLOMON, R L. & J. D. CORBIT.1974. An opponent-process theory ofmotivation: I. Temporal dynamics of affect. Psychol. Rev. 81: 119-145. J., H. DEWIT & R EIKELBOOM. 1984. Role of unconditioned and conditioned 5. STEWART, drug effects in the self-administration ofopiates and stimulants. Psychol. Rev. 91: 251-268. 6. WIKLER, A. & F. PESCOR.1967. Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid drinking behavior, and “relaps? in morphine-addicted rats. Psychopharrnacologia 10: 255-284. 7. MAX, B. 1990. This and that: Drug tolerance and great expectations. TIPS 11: 4 0 1 4 4 . 8 . ROBINSON, T. E. & J. B. BECKER.1986. Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis. Brain Res. Rev. 11: 157-198.
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9. KALIVAS,P. W. 1985. Sensitization to repeated enkephalin administration into the ventral tegmenml area of the rat: 11. Involvement of the mesolimbic dopamine system. J. Pharmacol. Exp. Ther. 235: 544-550. J. & P. VEZINA.1988. Conditioning and behavioral sensitization. In Sensitiza10. STEWART, tion in the Nervous System. P. W. Kalivas & C. D. Barnes, Eds.: 207-224. Telford Press. Caldwell, NJ. 11. WISE, R A. & M. A. BOZARTH.1987. A psychomotor stimulant theory of addiction. Psychol. Rev. 9 4 469-492. A. S. & B. S. BUNNEY. 1987. Activity of A9 and A10 dopaminergic neurons in 12. FREEMAN, unrestrained cats: Further characterization and e&cts of apomorphine and cholecystokinin. Brain Res. 405: 46-55. & M. J. ZIGMOND.1983. Environmental stimuli but not 13. KELLER, R W., E. M. STRIKER homeostatic challenges produce apparent increases in dopaminergic activity in the stnatum: An analysis by in vivo voltametry. Brain Res. 279: 159-170. 14. LOUILQT,A., M. LEMON, & H . SIMON.1986. Differential reactivity of dopaminergic neurons in the nucleus accumbens in response to different behavioral situations: An in vivo voltammetric study in the free moving rat. Brain Res. 397: 3 9 5 4 . 15. RDMO, R & W. SCHULTZ.1990. Dopamine neurons of the monkey midbrain: Contingencies of responses to active touch during self-initiated arm movements. J. Neurophysiol. 63: 592-606. 16. VEZINA,P. & J. STEWART.1984. Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA. Pharmacol. Biochem. Behav. 20: 925-934. 17. STEWART,J. & P.VEZINA.1987. Environment-specific enhancement of the hyperactivity induced by systemic or intra-VTA morphine injections of rats pre-exposed to arnphetamine. Psychobiology 15: 144-153. 18. VEZINA,P. & J. STEWART.1990. Amphetamine administered to the ventral tegmental area but not to the nucleus accumbens sensitizes rats to systemic morphine: Lack of conditioned effects. Brain Res. 516: 99-106. P. W. & B. WEBER.1988. Amphetamine injection into the ventral mesenceph19. KALIVAS, alon sensitizes rats to peripheral amphetamine and cocaine. J. Pharmacol. Exp. Ther. 245: 1095-1102. JR. 1981. Chronic D-amphetamine in nuJR., G. G. & E. H . ELLINWOOD, 20. DOUGHERTY, cleus accumbens: Lack of tolerance or reverse tolerance to locomotor activity. Life Sci. 28: 2295-2298. R J. & B. L. HAHN.1983. Pimozide blocks establishment but not expression 21. BENINGER, of amphetamine-produced environment-specific conditioning. Science 220: 1304-1306. 22. BENINGER, R J. & R S. HERZ. 1986. Pimozide blocks establishment but not expression of cocaine-produced environment-specific conditioning. Life Sci. 38: 1425-1431. 23. DREW,K. L. & S. D. GLICK.1990. Role of D-1 and D-2 receptor stimulation in sensitization to amphetamine-induced circling behavior and in expression and extinction of the Pavlovian conditioned response. Psychopharmacology 101: 465-471. & D. MWRMAN.1989. Context24. WEISS,S. R B., R M. POST, A. PERT,R WOODWARD dependent cocaine sensitization: Differential effect of haloperidol on development versus expression. Pharmacol. Biochem. Behav. 34: 655-661. 25. GOLD,L. H., N. R SWERDLOW& G. F. KOOB.1988. The role of mesolimbic dopamine in conditioned locomotion produced by amphetamine. Behav. Neurosci. 102: 544-552. & M. RODRIGUEZ.1987. Conditioned 26. BURUNAT,E., R CASTRO,M. D. DIAZ-PALARW response to apomorphine in nip-striaml system-lesioned rats: The origin of undrugged rotational response. Life Sci. 41: 1861-1866. 27. CAREY,R J. 1990. Dopamine receptors mediate drug-induced but not Pavlovian conditioned contralateral rotation in the unilateral U H D A animal model. Brain Res. 515: 292-298. B. A. & J. E. GO~SICK.1989. Conditioning and experiential factors affecting 28. MATITNGLY, the development of sensitization to apomorphine. Behav. Neurosci. 103: 1311-1317. B. A. & J. K. ROWLFIT.1989. Effects of repeated apomorphine and haloper29. MA-ITINGLY, idol treatments on subsequent behavioral sensitivity to apomorphine. Pharmacol. Biochem. Behav. 34: 345-347.
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30. MATTINGLY,B. A,, J. K. ROWLETT, J. GRAFF&G. LOVELL.1990. Effectsofselectivedopamine antagonists on the development of behavioral sensitization to apomorphine. Soc. Neurosci. Abst. 16: 253. 31. STEWART, J. & P. VEZINA.1989. Microinjections ofSCH-23390 into the ventral tegmenml area and substantia n i p pars reticulata attenuate the development of sensitization to the locomotor activating effects of systemic amphetamine. Brain Res. 495: 401-406. 32. VEZINA,P. & J. STEWART.1989. The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine. Brain Res. 499: 108-120. 33. HOFFMAN,D. C. & R A. WISE. 1990. Failure to observe cross-sensitization between the locomotor-activating effects of bromocriptine and cocaine or bromocriptine and heroin. Abst. Can. CoU. Neuropharm. 34. WISE, R A,, Personal Communication. 35. KARLER, R , L. D. CALDER,I. A. CHAUDHRY & S. A. TURKANIS. 1989. Blockade of"reverse tolerance" to cocaine and amphetamine by MK-801. Life Sci. 45: 599-606. 36. STEWART, J. & J. P. DRUHAN.1991. The non-competitive NMDA antagonist, MK801, blocks the development ofconditioned activity to amphetamine (AMPH). Soc. Neurosci. Abst. 37. WEIHMULLER, F. B., S. J. O'DELL, B. N. COLE& J. F. MARSHALL.MK-801 attenuates the dopaminc-releasingbut not the behavioral effects of methamphetamine: An in vivo microdialysis study. Brain Res. 549: 230-235. 38. TRUJILLO, K. A. & H. AKIL. 1991. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK801. Science 251: 85-87. 39. SIEGEL,S. 1975. Evidence from rats that morphine tolerance is a learned response. J. Comp. Physiol. Psychol. 89: 498-506. 40. SOBRERO,A. P. & M. E. BOUTON.1989. Effects of stimuli present during oral morphine administration on withdrawal and subsequent consumption. Psychobiology 17: 179-190. 41. ROFFMAN, M., C. REDDY& H. LAL. 1973. Control of morphine-withdrawal hypothermia by conditional stimuli. Psychopharmacologia 29: 197-201. 42. EIKELBOOM, R & J. STEWART.1979. Conditioned temperature effects using morphine as the unconditioned stimulus. Psychopharmacology 61: 31-38. R & J. STEWART. 1981. Conditioned temperature effects using amphetamine 43. EIKELBOOM, as the unconditioned stimulus. Psychopharmacology 75: 96-97. 44. STAIGER,P. K. & J. M. WHITE. 1988. Conditioned alcohol-like and alcohol-opposite responses in humans. Psychopharmacology 95: 87-91. 45. CHILDRESS,A., A. MCLELLAN & C. O'BIUEN.1986. Abstinent opiate abusers exhibit conditioned craving, conditioned withdrawal, and reductions in both through extinction. Br. J. Addiction 81: 655-660. 46. BOUTON, M. E. & D. SWARTZENTRUBER. 1991. Sources of relapse after extinction in Pavlovian and instrumental learning. Clin. Psychol. Rev. 11: 123-140. 47. STEWART, J. & P. VEZINA.1991. Extinction procedures abolish conditioned stimulus control but spare sensitized responding to amphetamine. Behav. Pharmacol. 2: 65-71. 48. STEWART, J., Unpublished data. 49. DE WIT, H. & J. STEWART.1981. Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75: 134-143. 50. DE WIT, H. & J. STEWART.1983. Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology 79: 29-31. 51. STEWART, J. 1984. Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area. Pharmacol. Biochem. Behav. 20: 917-923. 52. STEWART, J. & P. VEZINA.1988. A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior. Brain Res. 457: 287-294. 53. KALWAS, P. W. & J. STEWART.1991. Dopamine transmission in the initiation andexpression of drug- and stress-induced sensitization of motor activity. Brain Res. Rev. 16 223-244.
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related behaviors in two ways:by modifying the effects of drugs taken in their presence, and by eliciting conditioned effects that may contribute to relapse to drug-taking in drug-free individuals. In order to understand the contribution ofconditioning to drugrelated behaviors it w ill be important to determine which conditioned effects of drugs actually contribute to their abuse and how CSs gain the ability to control or modify the expression of drug actions.
CONDITIONED DRUG EFFECTS Pavlov* reporting on the experiments of a certain Dr. Krylov of the Tashkent Bacteriological Laboratory wrote: It is well known that the first effect of a hypodermic injection of morphine (in the dog) is to produce nausea with profuse secretion of saliva, tbllowed by vomiting, and then rotbund sleep. Dr. Krylov, however, observed when the injections were repeate regularly that after 5 or 6 days the preliminaries of injection were in themselves sufficient to produce all these sym toms-nausea, secretion of saliva, vomiting and sleep. Under these circumstancese!t symptoms are now the effect, not of the morphine acting through the blood stream directly on the vomitinB centre, but of all the external stimuli which previously had preceded the injection of morphine . . .
s
Pavlov continued,
. . . in the most striking cases all the symptoms could be produced by the dog simply seeing the experimenter. Where such a stimulus was insufficient it was necessary to open the box containing the syringe, to crop the fur over a small area of skin and wipe with alcohol, and erhaps even to inject some harmless fluid before the symptoms could be obtained: In the years since these observations were made, conditioned drug effects have been demonstrated to a wide range of centrally acting drugs and the potential importance of such effects for an understanding of the long-lasting consequences of drug use has been raised by numerous investigators.3" But although we continue to give lipservice to this view, little has been done to truly advance our understanding of these matters. There are steady advances in knowledge of the mechanisms of actions of various drugs of abuse; we are beginning to identify which actions of drugs are related to their abuse potential; and yet almost nothing is known about the mechanisms underlying the conditioning of these actions of drugs and how conditioned stimuli act to influence drug-taking behavior. What we lack are neural models to help us think about ways in which conditioned environmental stimuli can come to elicit drug effects or to modify the actions of drugs themselves.
If conalit3mring Lr to ocnc* to the E&s
of-s, Gmditbd Stimnli Must Haw Acuss to the Ccncral Neunal Ehaents Utublyhy Those E p t t S
Drugs may have effects on several response systems both within the central nervous system (CNS) and in the periphery. Some of the observed effects of drugs are produced directly by their action on central nervous system elements, whereas others are pmduced by their actions in the periphery. It is often found that drugs produce opposing changes depending on the time after injection and the dose administered. A high dose of morphine, for example, may produce hypothermia fbllowed by hyperthermia. It is
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important when trying to think about conditioned drug effects to realize that such biphasic effects could arise either from the output of two independent CNS systems, each directly activated by a drug, or from the output of a single CNS system responding to compensate fbr the initial drug action. The nature and direction of a conditioned drug effect, or conditioned response (CR), therefore, will not be easily predicted from the observed drug effects, but will depend on our knowledge of which CNS response systems are actually activated. If, as stated above, conditioning of a drug effect depends on the access of the neural elements excited by the CS to those CNS elements activated either directly or indirectly by the drug, it will be necessary to know how the drug effects are produced. Some conditioned drug effects will mimic the observed drug effect (so-called drug-like CRs) whereas others will oppose the observed drug effect (socalled drug-opposite CRs). In a recent issue of TIPS, B. Max,' though apparently interested in such effects, remarked scornfully that the problem with people working in the field is that they wanted to eat their cake and have it too; in other words, we wanted our conditioned drug effects both ways. We don't want them both ways, they are both ways, just as drug effects often are!
In studies of conditioned drug effects in animals, it has become standard to include at least three groups: a group which during the conditioning phase receives the drug on several occasions in the presence of a distinctive set of environmental stimuli (CSs) and saline in the absence of these stimuli (a PAIRED group), a group that receives saline in the presence of the distinctive stimuli and the drug injection in their absence (an UNPAIRED group), and a group that receives saline in both conditions (a CONTROL group). In a standard test for conditioning, all groups are presented with the CS in the absence of drug and the responses to the CS are compared. In a test for CS control of drug actions, all groups are given the drug in the presence of the CS and effects of the drug are compared. CS may act to diminish or to enhance the effect of a drug; the former can be referred to as the CS control of tolerance and the latter the CS control of sensitization.
CONDITIONING AND THE BEHAVIORAL ACTIVATING EPPECIS OF STIMULANT AND OPIOID DRUGS Common Nncral E h t s Undrrlic Somc of tbc Bebapimal Actions of
Stimulant and opioia L h g s Systemic injections of either amphetamine or cocaine lead to increased behavioral activation, locomotor activity and at higher doses to stereotypy, which with repeated injections shows sensitization.8 These effects are mediated by actions on the mesolimbic and striatal dopamine (DA) neurons where amphetamine increases extracellular DA by direct release and reuptake blockade, and cocaine by reuptake blockade. Acute systemic injections of medium to high doses of morphine produce in rats depressant effects fbllowed by excitatory effects. These are seen in the initial motor depression fbllowed by heightened locomotor activity. With repeated intermittent injec-
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tion the depressant actions show rapid tolerance revealing only the excitatory effects. The locomotor-activating effects of morphine can be elicited independently of the depressant actions, as shown by the direct application of morphine to the cell body regions of the mesolimbic and striatal dopamine (DA) neurons. Here morphine and other opioids act to increase firing in DA neurons thereby increasing extracellular dopamine in both cell body and terminal regions. As has been discussed in previous papers presented at this meeting, repeated injections of opioids lead, as do those of amphetamine and cocaine, to sensitization of the behavioral activating effects which appears to be mediated by long-term functional changes in the midbrain DA neuron^.^ When systemic injections of drugs h m either class are repeatedly paired with a set of environmental stimuli (CSs), increased locomotor activity is seen in the presence of these CSs when they are presented alone, that is, behavioral activation is elicited by the CSs. When repeated exposure to these drugs is paired exclusively with a set of environmental stimuli, the behavioral sensitization to the drugs is manifested only in the presence of these stimuli, that is, the expression of sensitization comes under CS control. 10 This set of findings should be of particular interest to those interested in the motivational effects of stimulant and opioid drugs and to the long-term consequences of their use. The mesolimbic DA system appears to be a behavioral ficilitatory system. Activity in this system promotes forward locomotion, enhances the behavioral effectiveness of positive incentive stimuli, and appears to underlie the motivational or rewarding properties of stimulant and opioid drugs as well as those of more natural positive incentives. l1 Sensitized hnctioning within this system could serve to enhance the response to stimuli having neural access to it. The fict that CSs are able to modulate the behavioral sensitization to drugs and to elicit drug-like behavioral activation in the absence of drugs implies that CSs may p n access directly to the facilitation system itself, i.e., the mesolimbic DA system, o r to those response systems activated by it, o r to both. These possibilities are shown in the diagram in FIGURE1. This diagram shows stimuli serving as CSs to have weak, but direct access to the ficilitation system. There is evidence for this from studies of responses of DA neurons to novel sensory stimuli. 12-15 Though these effects would normally habituate with repeated presenta-
cs
1
cs
2
RESPONSE
ucs
PIGURE 1. Diagram showing possible ways in which a conditional stimulus (CS)could gain access to neural units activated by an unconditioned stimulus (UCS). CSs neurons are shown to have weak, but direct access to a behavioral facilitation system normally activated by the UCS. The CSs are also shown to have access to some response units normally activated by the UCS via the facilitator. Changes in the behavioral effectiveness of a CS could be mediated by neural changes at either site through the co-occurrence of the CS and UCS (see text).
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tion, when a CS is paired with a UCS that activates the facilitator, the ability of the CS to activate the facilitator is strengthened or reinforced. In addition, the CS are shown to have access to certain response units normally activated by the UCS via the facilitator. Through repeated paired presentations of the CS and UCS, the capability of the CS to activate these responses would be strengthened by co-occurrence of activity in the CS neurons and the facilitator neurons. Either one or both of these mechanisms could underlie the conditioning of behavioral activation produced by the effects of drugs on the facilitator. Whether either or both of these effects underlies conditioned effects produced by a particular drug should depend on how that drug interacts with the DA facilitatory system to produce its unconditioned behavioral activational effect. Increased extracellular DA from midbrain DA neurons is common to the actions of morphine, amphetamine and cocaine. Increased extracellular DA at terminals is responsible for the behavioral activation produced by amphetamine and cocaine and, at least in part, for that produced by morphine; increased extracellular DA in the cell body region, appears to initiate processes responsible for the development of sensitization to these drugs, but we have not as yet identified the role of DA in conditioned activity to these drugs or in the CS control of the expression of behavioral sensitization to these drugs. As we explore what is known about conditioned effects, it is important to keep in mind how increased extracellular DA levels are achieved in the case of each drug. Morphine acts to increase DA cell firing causing impulse-dependent release. Cocaine interferes with the reuptake of DA, but release depends on impulses initiated by other means. In both cases the opportunity for concurrent activity in CS neurons and the DA neurons would exist making it possible that CS could come to activate DA neurons directly. The situation is less clear, however, for amphetamine which causes release directly, independent of firing in the DA neuron. In all three cases the possibility for CS-UCS interactions exist in the terminal regions of the DA neurons, either pre- or post-synaptically.
The locomotor activity elicited and the sensitization that develops when morphine is applied directly into the ventral t e p e n t a l area (VTA) can be brought under CS control. We showed that animals given pairings of the distinctive environment of an activity box and intra-VlX morphine (PAIRED) were more active in that environment compared to animals that received the same morphine injections elsewhere (UNPAIRED), or no morphine in either environment (CONTROL), when placed in it following placebo injections. Moreover, on a test for sensitization when d animals received intra-VTA morphine, only group PAIRED showed sensitization to the effects of morphine.16 Thus it appeared that repeated activation of the mesolimbic DA system in the presence of a specific set of environmental stimuli was a sufficient condition for the development of drug-induced conditioned activity and conditioned control of the expression of sensitized responding to intra-VTA morphine. We later showed that animals preexposed to systemic injections of amphetamine in the activity boxes were significantly more active in this environment on tests for cross-sensitization to morphine given either systemically or intra-VTA than were animals in either an UNPAIRED or CONTROL group. 17
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In an attempt to specify where the effects of the CS might interact with the unconditioned effects of these drugs to allow for conditioned activity and CS control of sensitization, we studied the development of sensitization to the effects of amphetamine injected directly into the VTA or the nucleus accumbens (NAC) using a conditioning paradigm.l8 Sensitization developed following repeated VTA amphetamine injections, as reported previously,19but there was no evidence for conditioned activity or for CS control of the expression of sensitization; sensitization did not develop following repeated NAC injections19JO nor was there evidence for conditioning. In this case, DA release and reuptake blockade from the somatodendritic region of the neurons, though sufficient for the development of sensitization, appeared not to engage the neural circuitry in a manner that allowed the integration of sensory information necessary for the development of CS control. In addition, excessive post-synaptic DA receptor stimulation in the NAC alone, led neither to conditioning of activity nor sensitization even though the animals were very active during drug exposure. These experiments are summarized in TABLE 1. It can be seen that only when DA neurons are activated to release DA from both somatodendritic regions and from their terminals allowing for feedback from postsynaptic regions can the interaction between sensory and drug-produced signals occur that is necessary for CSs to gun control of behavior. What we do not know is whether the CSs paired with these types of drug actions gain access, either directly or indirectly, to the DA cells. There is the possibility that the activity seen when the CS is presented alone or with drug is due to CS modification of activity in DA neurons per re, to learned modifications in circuits no longer DAdependent, or to both. There are several studies of the effects of DA antagonists on the CS control of sensitization and on conditioned activity that have tried to address this question. Pimozide, a non-selective antagonist, has been reported to block the development of conditioned activity based on amphetamine or cocaine, but not to block its expression; the effects on CS control of sensitization were not tested in these experiments.ZlJ2 In another experiment, however, conditioned circling based on amphetamine was found to be attenuated by both SCH-23390 and the D2 blocker metoclopramide.23 Weiss et aLZ4reported that haloperidol blocked the development, but not the expression of sensitization to cocaine, both of which were CS-dependent. Gold etal.25 showed that the expression of conditioned activity to amphetamine was blocked by 6-hydroxydopamine (6-OHDA) lesions of the mesolimbic DA system. These results suggest that DA neuron activity can be involved in both the development and expression of con-
TABLE 1. Summary of Data from Sensitization Experiments Using Systemic and Intracranial Injections of Amphetamine and Morphine Conditioned
DA Release Preexposure Drug Amphetamine i.p. Amphetamine VTA Amphetamine NAC Morphine i.p. Morphine VTA Morphine NAC
Cell Body
Terminal
+ +
+
-
+ +
Animal Active
Behavioral Sensitization
+
+ +
-
-
+ + +
+ + + +
Non-DA-dependent
+
+
-
Stimulus Control
+
-
+ + ?
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ditioned activity based on stimulant drug such as amphetamine and cocaine, but that under some conditions the conditioned activity can be DA-independent. Interestingly, the findings with the direct agonist, apomorphine, suggest that the conditioned response is DA-independent. It has been shown that in the unilaterally 6-OHDAlesioned rat, the direct DA receptor agonist, apomorphine, produces strong conditioned contralateral turning which was not blocked by haloperid01.M.~~ It is not clear from these studies, however, how apomorphine has its effects on turning in the unilaterally 6-OHDA-lesioned animal. It is possible that the remaining intact contralateral DA system or residual fibers on the lesioned side are involved. The hct that the unconditioned and the conditioned effects were obtained with .05 mgkg apomorphine, an autoreceptor selective dose, which could increase contralateral turning by inhibiting firing and DA release on the non-lesioned side, and that the conditioned effects were most obvious six weeks post su’gery, at a time when compensatory changes in remaining fibers would have occurred, supports this idea. There is a growing literature on conditioning and sensitization in normal animals with direct DA agonists including the mixed Dl/D2 agonist, apom0rphine.2~J~Mattingly30 has shown recently that sensitization to apomorphine, as has previously been shown for amphetamine23.31.32 is blocked by the D1 antagonist, SCH-23390, but not by a selective D2 antagonist. The D2 selective agonist, bromocriptine33 also leads to sensitization that is completely under CS control and is not blocked by the DI antagonist. It appears that sensitization and conditioning induced by these direct acting drugs may be mediated differently from each other and from that fbund with the indirectly acting stimulants. For example, there is no cross-sensitization between bromocriptine and cocaine or heroin.” Although considerable work will be required for an understanding of the bases of these differences, it does appear that there are conditioned changes that are dependent on the DA system fbr their expression and others that are not. It may be that CSs gain access to circuits involved in the activation of DA neurons at the somatodendritic region or in the release of DA directly from terminals, and to circuits that are modulated by DA during learning, but that once modified are DA-independent. Conditioned behavioral hcilitation produced by CSpairings with drugs such as morphine, amphetamine, and cocaine probably involve both types of circuits: The situation may be different in the case of direct DA agonists which do not cause DA release either directly or indirectly.
It has been reported35 that systemic injections of the noncompetitive N-methyl+ aspartate (NMDA) receptor antagonist, MK801, block the development of sensitization to both amphetamine and cocaine implicating the actions of excitatory amino acids (EAA) at NMDA receptors in the plastic changes brought about by repeated drug administration. Because of the known role of NMDA receptors in several instances of learning, we considered that MK801 might be acting by blocking conditioning of behavioral activation rather than the development of sensitization pc’ sc. Using the two sets of the usual three groups, PAIRED, UNPAIRED and CONTROL, one pretreated with MK801 and the other with saline during the conditioning phase, we showed that in the MK801-pretreated groups there was no evidence for conditioned activity on the test fbr Conditioning, nor was there any evidence fbr sensitization when
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these animals were tested with amphetamine alone.% We can say h m this experiment that MK801 blocked the development of conditioned activity, however, we cannot determine whether sensitization was blocked independently from conditioning, or whether MK801 interfered with the effectivenessofamphetamine as a UCS (but see ref. 37). In order to do this, a sensitization paradigm that does not allow for the possibility of conditioned effects must be used. Experiments are currently under way in our laboratory to explore this question. The idea, however, that MK801 interferes with conditioning of the drug effect is supported by the results of a recently reported experiment38 in which it was fbund, using a morphine treatment regimen known to produce environment-specific analgesic tolerance,39that MK801 blocked the development of tolerance to the analgesic effects of morphine, without affecting analgesia pw re.
A ROLE FOR CONDITIONED DRUG EFFECTS IN DRUG-TAKING It has long been proposed that conditioned drug effects play a role in relapse to drug-taking in experienced, drug-free individuals. Two kinds of conditioned effects have been proposed to play such a role: drug-opposite effects or those associated with withdrawal, and drug-like effects. Drug-opposite conditioned effects are said to precipitate drug-taking by creating aversive symptoms resembling withdrawal,3*6whereas drug-like effects are said to create a positive motivational state, enhancing the incentive value of drug-related stimuli, and thereby increasing the probability of drug-related thoughts and action^.^ Both types of conditioned effects have been shown to occur. However, studies done in animals in search of evidence that conditioned aversive effects lead to drug-taking have been unsuccesshl (see ref. 5 for a review and ref. 39). On the other hand, numerous studies have shown that animals seek out places associated with drugs and respond persistently to stimuli associated with them. Conditioning of the unconditioned reinforcing and behavioral activating effects of opioid and stimulant drugs occurs readily. These unconditioned drug effects are mediated at least in part by the mesolimbic DA system and that activity in this system is increased by natural incentives and in turn enhances the effectivenessof incentive stimuli. These observations taken together lead logically to the hypothesis that CSs associated with these drugs might increase activity in this system and thus serve to increase the probability of drug-taking behaviors.
c m t a i k d Drug E F s in Witbdnzwal and *a
Abstinence
In an early study of the conditioned effects of opioids, it was shown in rats that presentation of a CS that had been paired repeatedly with morphine could reverse the decrease in body temperature that accompanies withdrawal from morphine.41 Animals were maintained on high doses of morphine and then the drug was abruptly withdrawn. Core temperature was measured every 12 hours over three subsequent days. Presentation of the bell CS was able to reverne the withdrawal precipitated hypothermia. In a subsequent study the conditioning of body temperature changes produced by morphine was observed both during the period of repeated daily morphine injections and after a period of a b ~ t i n e n c eGroups .~~ of animals were given injections of either 0, 5, 25, or escalating to 100 mg/kg morphine i.p. The daily routine was to
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measure temperature at 09:OOh in the home cage (HC), to transport the animals to a distinctive preinjection environment (PreINJ) at 10:00h, to measure their temperature there at ll:OOh, to transport them to a distinctively different injection environment (INJ) at 12:OOh and to give the daily injection immediately. Temperature was measured at 12:45 and at 14:15h in the injection environment. During the conditioning phase, animals in the morphine treatment groups were hypothermic at 11:OOh in PreINJ compared to control group animals and compared to themselves at 11:OOh in the HC. This effect, seen 23 hours after the previous morphine injection, suggested a withdrawal-like hypothermia which was subsequently shown to be precipitated by the time of day and to be exaggerated by the PreINJ mom cues. Following a period of abstinence, this preINJ hypothermia was n o longer evident, but when animals were placed in INJ and given saline, body temperature rose and marked hyperthermia relative to control group animals was seen at 12:45h and 14:15h. This experiment demonstrates that CSs previously paired with morphine injections caused conditioned hyperthermia (an excitatory drug-like CR) in drug-free animals after a prolonged period of abstinence. A very similar pattern of results was obtained when amphetamine was used as the drug for conditioning43 An interesting parallel to these findings was found in a recent study o n conditioned heart rate changes to ethanol.44 Volunteer social drinkers were given discriminative conditioning to ethanol using a combination of a distinctive room and a flavored drink as Css. During the period of conditioning, subjects were brought into one of the rooms and then given a flavored drink containing ethanol; in the other room a different flavored drink contained no ethanol. Heart rate rose in response to ethanol and remained higher than that of control subjects over the 30 minute test period. O n the tests for conditioning, subjects were presented with each of the CSs alone or in combination. Presentation of the Room alone led to a decrease in heart rate from baseline. Presentation of the Flavored Drink (in a neutral room) led to a sharp increase in heart rate; the combination of cues Room then Drink led to changes that were similar to the Room alone. This study points out that not only can opposite conditioned responses be obtained, but that different elements of the stimulus complex may lead to different conditioned responses. In this case the stimulus most proximal to and that best predicted the ethanol led to a response that mimicked the unconditioned effect of the drug. It would have been interesting to see what would have happened to the two responses as the time between the original conditioning trials and the tests increased.
Repeated presentation of a CS in the absence of the unconditioned stimulus leads to the reduction and elimination of the CR. This phenomenon, known as extinction,
has been the basis of various therapies aimed at eliminating conditioned drug effects;45the assumption being that conditioned drug effects play a role in drug-taking and in relapse to drug-taking after abstinence. CRs are known to be resistant to change and are not eliminated without extinction training. Furthermore, extinction is a fragile process and does not erase the original learning. Extinguished responses are found to recover “spontaneously” with the passage of time and to be easily reinstated by a single CS-UCS pairing. Bouton& has shown in a series of experiments that extinction makes behavior especially sensitive to the background or context in which extinction
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occurs. A response may appear to be eliminated by extinction trials in one context, only to be fully reinstated in another. Contextual cues as diverse as physical environments, drug states and emotions can reinstate the ability of CSs to elicit CRs. In our studies of the CS control of the expression of sensitization of the locomotor effects of am~hetarnine4~ and m0rphine,4~we studied the effects of extinction training o n previously established CS control of sensitization. The three standard groups were used in each experiment (groups PAIRED, UNPAIRED, and CONTROL). Conditioned activity and CS control of sensitization were both evident o n tests made following CS drug pairings. A series of extinction sessions followed during which all groups were tested repeatedly in the activity boxes, but after being given saline injections only both in the activity boxes and in the home cages. By the last day of extinction there were n o differences in activity between groups, it-., n o evidence of conditioning. O n the tests for sensitization which followed, however, in which all animals were given drug before going into the activity boxes, sensitized responding was reinstated. In the case of morphine, animals in group PAIRED were once again significantly more active than animals in the other two groups. Interestingly in the case ofamphetamine, both group PAIRED and UNPAIRED were now more active than CONTROL, suggesting that the extinction sessions had eliminated the inhibition of the expression of sensitization previously seen in group UNPAIRED when tested in the CS-environment. These findings are reminiscent of those from experiments o n reinstatement of drug self-administration. In these experiments it is found that, following a period of extinction in which responding is n o longer reinforced, noncontingent injections of the drug reinstate drug-taking behavior, suggesting that the drug reinstates the effectiveness of drug-related stimuli, or CSs.49-52 These findings show that, in spite of extensive extinction experience in which conditioned stimuli are repeatedly presented in the absence of drug, the effectiveness of such stimuli is easily reinstated by simple re-exposure to the drug in their presence. There is also good reason to think that exposure to other similarly acting drugs and to stresson, both of which show cross-sensitization (see ref. 53), and the arousal of strong positive emotions could all act to reinstate the effectiveness of these stimuli.
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