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Reprinted from D. van der Kooy  (1987), Place conditioning: A simple and effective method for assessing the motivational properties of drugs. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 229-240). New York: Springer-Verlag.
 
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Chapter 13

Place Conditioning: A Simple and Effective Method
for Assessing the Motivational Properties of Drugs
 

Derek van der Kooy

Department of Anatomy
University of Toronto
Toronto, Ontario, Canada M5S 1A8


Abstract
The advantages of the place conditioning paradigm for assessing the reinforcing properties of drugs are presented from historical, procedural, and parametric viewpoints. The importance of employing a "balanced" paradigm is emphasized. The potential of the paradigm to answer basic questions concerning the neural bases of motivation is outlined with examples.

 

Introduction

Almost all assessments of the reinforcing properties of stimuli in nonhuman animals depend on learning paradigms. The exceptions involve studying the effects of noncontingent administration of drug reinforcers on ongoing species-typical behaviors such as feeding or locomotion. However, the inferences that the effects of the reinforcing stimuli in these studies are actually due to changes in motivation are very tenuous. In learning paradigms the assessments of the reinforcing properties of stimuli can be classified as either indirect or direct. In the indirect assessment paradigms, animals can be trained to make responses for a reinforcer such as intracranial self-stimulation (see Esposito, Porrino, & Seeger, this volume; Reid, this volume), and then the effects of the reinforcing stimulus of interest (such as a drug) are studied against the baseline responding. Again, the inference is not always obvious that the effects of the drug on baseline responding are due to changes in motivation rather than nonspecific sensory or motor changes.

In the direct assessments paradigms, the essential manipulation is that animals associate a certain stimulus or response with a drug stimulus. This association, in the case of a response learning, produces increased responding for a positive reinforcing drug such as occurs in the self-administration paradigm (see Roberts & Zito, this volume; Yokel, this volume). The association of a positive reinforcing drug with stimuli in the environment produces an increased preference for specific environmental stimuli as opposed to other similar stimuli (this chapter; Phillips & Fibiger, this volume). In both direct assessment paradigms (self-administration and place conditioning), one can formally understand the pairing of the reinforcing drug stimulus as either stimulus-stimulus or stimulus-response depending on one’s theoretical view of what is associated during learning. Thus, for example, the lever-pressing self-administration procedure can be seen as animals continually maneuvering themselves as close as possible to stimuli (those proximal to the lever) associated with the drug reinforcer; on the other hand, the place conditioning procedure can be seen as increased locomotor responses to the environment associated with the drug reinforcer. I will argue that place conditioning involves the simplest and quickest association with drug reinforcers and thus minimizes the ambiguity of learning paradigms that inevitably complicate the interpretation of even the direct drug reinforcement assessment procedures. In the following description of the place conditioning method, a number of advantages of the paradigm for assessing the reinforcing properties of drugs will be illustrated. These include the method’s rapidity, sensitivity, accurate generation of dose-response curves, avoidance of subject testing under the drug stimulus, possibility of centrally administering drugs, study of both positive reinforcing and aversive properties of drugs, and precise control of the temporal association of drugs with stimuli. Finally, the use of place conditioning to explore two substantive problems in the drug reinforcement field (i.e., the paradoxical reinforcing effects of morphine and the motivational vs. satiety effects of cholecystokinin) will be detailed.

History of Place Conditioning

The history of the place conditioning method is the history of animal conditioning paradigms and can be seen to date from the late 1800s with Thorndike who was the first to establish formal learning paradigms for animals in the laboratory. Thorndike (1911) trained animals to go to a place in a box, to unlock a latch, and to escape. The first use of a place conditioning procedure similar to the one in current use may be that of Garcia, Kimeldorf, and Hunt (1957) who exposed rats to ionizing radiation in a distinctive environment and showed a clear aversion to the cues of this environment. A procedure employing arm choice in a Y-maze, which has some conceptual similarities to the place conditioning method, was first used in 1957 (Beach, 1957) to demonstrate the positive reinforcing properties of morphine. This demonstration predated the classic self-administration study by Weeks (1962) showing operant responding for intravenous morphine injections in rats.

In most place conditioning procedures, animals are treated by explicitly pairing distinctive environmental cues with administration of a drug. The animals are later tested by being presented with an opportunity to spend time in the presence of cues paired with the drug or in the presence of cues not paired with the drug. Animals prefer to spend time in environments paired with a number of drugs that can be classified as positive reinforcers. These include food (Stapleton, Lind, Merriman, Bozarth, & Reid, 1979; Swerdlow, van der Kooy, Koob, & Wenger, 1983), opiates (Bozarth & Wise, 1981; Katz & Gormezano, 1979; Mucha, van der Kooy, O’Shaughnessy, & Bucenieks, 1982; Phillips & Le Paine, 1980; Rossi & Reid, 1976; Sherman, 1980; van der Kooy, Mucha, O’Shaughnessy, & Bucenieks, 1982), amphetamine (Reicher & Holman, 1977; Sherman, Roberts, Roskam, & Holman, 1980b; Spyraki, Fibiger, & Phillips, 1982a), cocaine (Mucha et al., 1982; Spyraki, Fibiger, & Phillips, 1982b), and apomorphine (Spyraki et al., 1982a; van der Kooy, Swerdlow, & Koob, 1983b). On the other hand, animals avoid environments paired with drugs that can be considered aversive. These include lithium chloride (Mucha et al., 1982), naloxone (Mucha et al., 1982), vasopressin (Ettenberg, van der Kooy, Le Moal, Koob, & Bloom, 1983) and cholecystokinin (Swerdlow et al., 1983).

It is important to note that reports exist of both conditioned place preferences and conditioned place aversions with some drugs. Thus, although preferences are usually seen with amphetamine (Reicher & Holman, 1977; Sherman et al., 1980b; Spyraki et al., 1982b), aversions have also been reported (Martin & Ellinwood, 1974). Similarly, ethanol appears to produce mainly place aversions (Cunningham, 1980; van der Kooy, O’Shaughnessy, Mucha, & Kalant, 1983a), but there is also one report of the conditioning of place preferences (Black, Albiniak, Davis, & Schumpert, 1973). Finally, place preferences are usually seen with apomorphine (Spyraki et al, 1982a; van der Kooy et al., 1983b), but conditioned place aversions also have been seen (Best & Mickley, 1973). In recent work employing intravenous apomorphine administration over a wide dose range, we have primarily seen no motivational effects, neither preferences nor aversions (Mackey & van der Kooy, unpublished observations). One view of these contradictory results is to see the place conditioning paradigm as inherently unreliable. Another viewpoint emphasizes that the three drugs mentioned above (amphetamine, alcohol, and apomorphine) are among the best examples of drugs previously shown (Wise, Yokel, & de Wit, 1976) to have paradoxical reinforcing properties (i.e., positive reinforcing properties as measured in the intravenous self-administration paradigm and yet over the same dose range aversive properties as measured in the conditioned taste aversion paradigm). Thus, perhaps the place preference paradigm can measure both the positive reinforcing and aversive properties of the same drug depending on subtle (and as of yet unknown) procedural differences during conditioning.

For the most part, drugs that are self-administered intravenously by animals also produce place preferences. However, there are some differences between the two methods with certain drugs. For example, dopamine-receptor blockade with neuroleptics attenuates the positive reinforcing effects of cocaine in the self-administration paradigm (de Wit & Wise, 1977) but not the place preference paradigm (Mackey & van der Kooy, 1985; Spyraki et al., 1982b). From one viewpoint this result attests to the exquisite sensitivity of the place preference paradigm; it detects positive reinforcing effects in addition to those blocked by neuroleptics.

Procedural Issues

Place conditioning is really a misnomer for the paradigm under discussion. There is not a stored memory of environmental cues forming a spatial map as in paradigms such as the radial arm maze or Morris water task. In the place conditioning paradigm, as it is routinely used in drug reinforcement studies, rats are tested for their preferences for different environmental cues that are constantly present during testing. In the variation of place conditioning that we use, considerable effort is extended to offer the rat choices between distinctive yet equivalent cues. Thus one side of the box is black with a black Plexiglas floor and a slight smell of vinegar, and the other side is white with a wire mesh floor covered with sawdust. This combination of stimulus choices results in naive rats having no natural or baseline preference for either type of environment. Thus we can counterbalance our drug pairings with half the rats in any experimental condition receiving drug treatments in the black box and vehicle control treatments in the white box, and vice versa for the other half. This counterbalancing is an important point. Other experimenters employ conditioned stimuli that produce a strong "natural" preference for one environment with the result that the drug pairings are almost always with the least preferred side (Ceiling effects usually preclude observing drug conditioned increases in time spent on the preferred side.). Different and sometimes suspicious (see below) results are occasionally seen with "unbalanced" place conditioning paradigms as compared with the "balanced" paradigm we routinely employed.

As noted above, place conditioning is actually conditioning with the differing visual, tactile, and olfactory cues of the two environments. It will be important in the future to determine which modality of sensory stimuli is capturing most of the associative value from the paired drug. For example, rats always show a preference for the visual, tactile, and olfactory cues of the environment paired with morphine (Mucha et al., 1982). Other experimenters report place preferences when morphine is paired with only visual (Rossi & Reid, 1976) or visual and tactile (Bozarth & Wise, 1981; Phillips & Le Paine, 1980) stimuli; however, it is difficult to determine whether these paradigms are as sensitive in revealing the positive reinforcing properties of morphine as paradigms employing visual, tactile, and olfactory conditioned stimuli. On the other hand, when morphine is paired with taste stimuli, as in conditioned taste aversion paradigms, rats avoid the stimulus paired with morphine (Sherman et al., 1980a; van der Kooy & Phillips, 1977). Thus, the motivational properties of morphine seem to depend on the conditioned stimuli used to reveal these properties. A clear understanding of the stimulus modality most important in morphine place conditioning may help in pinpointing the differential associability issue and indeed in solving the problem of the paradoxical reinforcing effects of morphine.

Parametric Data

Place conditioning has been studied most thoroughly by experimenters using morphine as the reinforcing stimulus. Morphine produces place preferences (see Figure 1) over its entire usable dose range (Mucha et al., 1982). A low dose of 0.08 mg/kg (i.v.) produces a preference for the environment in which it was paired (four training trials) although this dose does not produce detectable effects on locomotion or analgesia (measured in the tail flick test) in our hands. More sensitive tests for locomotor or analgesic actions may have revealed effects at this low dose of morphine. High doses (10 and 15 mg/kg, i.v.) also produce strong place preferences, although the animals show marked immobility at these doses which are approaching the lethal range for opiate naive rats. Figure 1 shows that the steep part of the dose-response curve occurs between 0.01 and 0.08 mg/kg (i.v.), although there is a more gentle rise from 0.08 to 10 mg/kg. This can be best appreciated by comparing the differences between the times in the morphine- and saline-paired sides over the dose range. The steep part of the dose response curve for subcutaneously administered morphine occurs between 0.04 and 1.0 mg/kg (Mucha & Iversen, 1985). Thus, place conditioning is a very sensitive measure of the low threshold dose of systemic morphine required for positive reinforcing effects and also shows that there is a gentle increase in the positive reinforcing value of morphine over its entire usable dose range.

Place preferences for morphine can be produced with as little as one pairing of the drug with a distinctive environment (and one pairing of the saline vehicle with the alternate environment; Mucha et al., 1982). In addition, it has recently been shown that after three pairings of morphine with a distinctive environment, the conditioned preferences for that environment were retained for at least one month (Mucha & Iversen, 1985). These properties of one trial learning and long retention suggest that the power and robustness of the place conditioning paradigm for measuring the positive qualities of a drug’s reinforcement may be similar to that of the much touted conditioned taste aversion paradigm for measuring the aversive qualities of drugs.

The small numbers of drug pairings necessary in place conditioning is a particular advantage when injections of drugs into the cerebral ventricles (see Figure 2) or brain tissue (see Figure 3) are employed. Damage to the injected brain tissue is a danger especially when large numbers of microinjections are used. A number of investigators have demonstrated place preferences after microinjections of opiates into the ventral tegmental area (Phillips & Le Paine, 1980, 1982), nucleus accumbens (van der Kooy et al., 1982) and periaqueductal gray (van der Kooy et al., 1982). Microinjections of opiates in a number of other areas fail to produce place conditioning (van der Kooy et al., 1982). These studies provide the initial attempt to map specific brain systems where opiates act through their receptors to produce positive reinforcing effects. The place preferences produced by brain microinjections of opiates show stereospecificity, and this provides evidence that a specific opiate receptor is involved (van der Kooy et al., 1982). The possibility of directly probing the neural substrates of motivation with a minimal number of brain microinjections is one of the major advantages of the place preference paradigm.
 

 
Morphine dose-response analysis
Figure 1: Time spent on the sides of the test box paired with saline and with morphine for rats (n = 8 to 14) treated with different morphine (i.v.) doses. The data were collapsed across the two times in the treatment box. Reprinted with permission from Mucha, Bucenieks, O’Shaughnessy, and van der Kooy, 1982. Copyright 1982 by Elsevier Biomedical Press.
 

 
 
CPP from intraventricular morphine
Figure 2: Time spent on the side of the test box paired with saline or morphine for rats given morphine into different cerebroventricular sites and in different doses. The number of animals in each group is indicated near the bottom of each bar. The asterisk indicates that a significant (p < 0.05) place preference was seen. There was also a trend to a significant place preference when 10 mg of morphine was microinjected into the IIIrd ventricle. Reprinted with permission from van der Kooy, Bucenieks, Mucha, and O’Shaughnessy, 1982. Copyright 1982 by Elsevier Biomedical Press.
 

 
 
CPP from morphine micorinjected into various brain sites
Figure 3: Mean increase of time on the side of the test box paired with morphine (test minus pretest in an unbalanced paradigm) at various cannulae placement sites. The number of animals at each placement site is indicated near the bottom of the corresponding bar. The asterisks indicate that a significant (p < 0.05) increase in time spent on the side of the test box paired with morphine was produced by place conditioning. Reprinted with permission from vander Kooy, Bucenieks, Mucha, and O’Shaughnessy, 1982. Copyright 1982 by Elsevier Biomedical Press.
 

Unlike some of the indirect methods for assessing the positive reinforcing properties of drugs, place conditioning appears to permit no interpretations of conditioned preferences other than the fact that the drug stimulus has positive reinforcing properties. Testing in place conditioning is done drug-free. This eliminates the problem (in many indirect paradigms) of measuring drug reinforcement while subjects are under the influence of drugs producing various sensory and/or motor changes which can confound and interfere with the reinforcement measurements. The only other conceivable explanation of place preferences might involve the motivational effects of novelty in combination with memory deficits or state-dependent learning. For example, the drug-paired side may not be recalled during testing, because training is under the influence of that drug whereas testing is in its absence. Rats may then spend more time in the presence of the drug-paired cues on the test because these cues are perceived as novel and, for this reason of novelty, possibly positively reinforcing (Berlyne, 1969). These explanations for place preference are untenable for two reasons. First, testing under state-dependent conditions (i.e., under the influence of the drug) produces results no different from those run under normal drug-free testing conditions (Mucha et al., 1982; Mucha & Iversen, 1985). Second, no motivational effects of novelty were seen in the place conditioning paradigm. Rats showed no preferences in place conditioning tests for a novel side over one experienced previously (Mucha & Iversen, 1985; Mucha et al., 1982). Furthermore, when tested in a three-compartment box (the third compartment being novel), rats still preferred the morphine-paired compartment (Mucha & Iversen, 1985).

Different Ways to Run Place Conditioning

There are two ways (i.e., balanced and unbalanced) to do place conditioning. In the balanced paradigm care is taken to choose conditioning stimuli that produce approximately equal preferences for the two sides of the test compartment in naive, untreated rats. This permits counterbalancing of drug pairing with one side of the conditioning box within a group and also obviates the need for pretesting subjects before training begins. In the unbalanced paradigm subjects are pretested and usually show a substantial preference for one side of the test box. Drug pairings are then always on the least preferred side. Because counterbalancing is impossible, a separate control group is often run with vehicle injections to demonstrate that increases in time on the least preferred side are not as large with saline as with morphine (Bozarth & Wise, 1981; Katz & Gormezano, 1980; Phillips & Le Paine, 1980, 1982). Even with morphine, absolute preferences are not often produced in the unbalanced paradigm, just relative increases in time in the least preferred side.

The results of place conditioning studies can vary depending on whether balanced or unbalanced paradigms are used. With the balanced paradigm clear aversions to naloxone (see Figure 4) are observed in both morphine pretreated and morphine naive rats (Mucha et al., 1982). Unbalanced paradigms have generally failed to show conditioned naloxone aversions (Bozarth & Wise, 1981; Phillips & Le Paine, 1980, 1982). Part of the inability to see aversive effects may reflect a baseline problem; naloxone is usually paired with the least preferred side of the test box and an aversion can only be seen by an even greater avoidance of this side.

However, there are more substantial differences between balanced and unbalanced paradigms than can be explained by baseline or ceiling problems. In line with dopamine theories of reward, there have been reports that neuroleptic administration in the unbalanced paradigm blocks the place preferences produced by opiates (Bozarth and Wise, 1981). Employing a balanced paradigm, we have been unable to block with high doses of haloperidol or a-flupenthixol the place preferences produced by various doses of morphine (Mackey & van der Kooy, 1985). At present there is no convincing explanation for these differences. One possible explanation is that the unbalanced paradigm does not really (or at least not only) measure the positive reinforcing properties of morphine. As mentioned above, the normal control group tested in the unbalanced paradigm is one in which saline is paired with the least preferred side, and the increase in time on that side at testing is not as large as when morphine is used. However, this may not be the appropriate control for morphine treatment in the unbalanced paradigm. Because morphine treatment cannot be counterbalanced with both sides of the conditioning box in the unbalanced paradigm, there is no intrinsic control for morphine pairing with the general training environments (test room, handling, common properties of both training compartments). In fact, when an appropriate control is done (pairing of morphine with the least preferred side, preferred side, and general test environment), then increases in time on least preferred side at testing are similar to those seen with rats that received the same number of doses of morphine but only on the least preferred side (Mucha & Iversen, 1985). Presumably, in the unbalanced paradigm morphine is being associated with the entire test environment and the increased time on the least preferred side at testing simply reflects less anxiety about or avoidance of aversive aspects of the conditioned environment. In light of this it is not surprising that experimental differences are seen when the unbalanced paradigm is compared to the balanced paradigm which appears to measure strictly the positive reinforcing properties of the drug stimulus.
 

 
Effect of naloxone in morphine dependent and morphine naive rats
Figure 4: Difference between mean time spent on the side of the test box paired with different doses of naloxone and the mean time spent on the side of the test box paired with saline in morphine naive (circles) and morphine pellet implanted (triangles) rats (n = 5 to 17). Abscissa is a log scale. Reprinted with permission from Mucha, Bucenieks, O’Shaughnessy, and van der Kooy, 1982. Copyright 1982 by Elsevier Biomedical Press.
 

Use of Place Conditioning to Study Problems
in Drug Reinforcement

A major advantage of the place conditioning paradigm over other methods of measuring the reinforcing properties of stimuli is its sensitivity to both the aversive and positive reinforcing properties of drugs. This attribute has allowed the testing of some important questions in the area of motivation. Two examples are described below.

Satiety Versus Aversive Effects of Cholecystokinin

Feeding in food-deprived animals is reduced by injection of cholecystokinin (CCK) in a dose-dependent manner (Gibbs, Young, & Smith, 1973). This evidence has been interpreted either in terms of CCK involvement in satiety (Gibbs et al., 1973) or in terms of a CCK-induced malaise (Deutsch & Hardy, 1977).

These two hypotheses imply opposite predictions concerning the motivational properties of CCK in food-deprived animals. According to the CCK-satiety hypothesis, CCK should reduce the hunger of food-deprived animals. Therefore, hungry rats should learn to prefer an environment associated with CCK over one not associated with CCK. Moreover, sated rats should not learn this preference. On the other hand, according to the CCK-malaise hypothesis, CCK should have only aversive properties in both food-deprived and sated animals. All rats, hungry or not, should therefore learn to avoid environments associated with CCK. We tested these hypotheses using the conditioned place-preference paradigm (Swerdlow, van der Kooy, Koob, & Wenger, 1983). Both food-deprived and sated rats exhibited a dose-dependent conditioned place aversion to CCK (see Figure 5). The malaise interpretation of CCK’s effect was therefore supported (Swerdlow et al., 1983). Thus, the sensitive bidirectional properties of the place conditioning paradigm enabled its use as an independent test of the opposite predictions made by two competing theories concerning CCK’s action.
 

 
Place conditioning from CCK
Figure 5: Time spent in environments previously paired with  CCK (solid) or saline (stippled) shown as a function of conditioning dose of CCK. All injections were given intraperitoneally in a volume of 3 ml/kg to promote diffusion into the peritoneal cavity. Measurements were made during a 10-minute test period following 8 days of conditioning of (A) sated or (B) food-deprived animals. The value at each dose represents scores from a separate group of six animals. Rats were tested drug-free. Reprinted with permission from Swerdlow, Koob, van der Kooy, and Wenger, 1983. Copyright 1983 by Pergamon Press.
 

Paradoxical Reinforcing Effects of Opiates

As mentioned above, opiates have been shown to have paradoxical reinforcing qualities—positive reinforcing as measured in the conditioned place preference paradigm and aversive as measured in the conditioned taste aversion paradigm. Recent work showing opiate receptors on primary sensory neurons led us to test the motivational effects of local peripheral administration of opiates. In both the ear scratch and hot plates tests, a local, naloxone-reversible hyperalgesic effect of etorphine was observed (van der Kooy & Nagy, 1985). Thus, we hypothesized that the positive reinforcing properties of opiates are mediated by an action at central opiate receptors (see Figures 2 and 3) whereas the aversive effects of opiates may be mediated by an action at peripherally located opiate receptors. The possibility of measuring both positive reinforcing and aversive effects in the place conditioning paradigm and the availability of naltrexone and its quaternary derivative methyl naltrexone, which does not cross the blood-brain barrier effectively (Valentino, Herling, Woods, Medzihradshy, & Merz, 1981), provided the opportunity to test the hypothesis.

Systemic naloxone has been previously shown to produce place aversions (see Figure 4) in drug naive rats (Mucha et al., 1982). Presumably this aversive effect is due to an antagonism by naloxone of endogenous opioid peptides acting primarily on the dense concentrations of brain opiate receptors. We predicted that systemically administered naltrexone (an opiate antagonist similar to, but longer lasting than, naloxone) would have the same aversive effect. We further predicted that this action on central opiate receptors would overwhelm any action on the much smaller population of peripheral opiate receptors. However, methyl naltrexone, which does not cross the blood-brain barrier effectively, would be expected to primarily block the action of endogenous opiate peptides in peripheral opiate receptors. If the normal action of opiate peptides in the periphery is an aversive or hyperalgesic one, then methyl naltrexone would be predicted to cause conditioned place preferences. Indeed, these predictions were confirmed (Bechara & van der Kooy, 1985). Both subcutaneous and intraperitoneal naltrexone produced dose-dependent conditioned place aversions, whereas both subcutaneous and intraperitoneal methyl naltrexone produced dose-dependent conditioned place preferences. Thus, studies with the place conditioning paradigm provide strong support for the hypothesis that opiates work at central receptors to produce positive reinforcing effects and at peripheral receptors to produce aversive effects.

In conclusion, the place conditioning paradigm provides a rapid, simple, and elegant method of measuring the positive reinforcing or aversive properties of both peripherally and centrally administered drugs. In doing so, the paradigm offers a potent approach to basic questions concerning the neural basis of motivation.

Acknowledgments

The author acknowledges the wonderful collaboration in the place conditioning studies mentioned of a number of colleagues, including Tony Bechara, Peter Bucenieks, Aaron Ettenberg, Martha O’Shaughnessy, Harold Kalant, George Koob, Bruce Mackey, Ron Mucha, Neal Swerdlow, and John Wenger. Special thanks to Ron Mucha for innumerable discussions. Thanks also to Dr. H. Merz for his generous gift of methyl naltrexone. This research was supported by grants to the author from the Medical Research Council of Canada and the Natural Sciences and Engineering Research Council of Canada.

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