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Reprinted from N.M. White, C. Messier, and G.D. Carr (1987), Operationalizing and measuring the organizing influence of drugs on behavior. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 591-617). New York: Springer-Verlag.
 
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Chapter 28

Operationalizing and Measuring the Organizing
Influence of Drugs on Behavior
 

Norman M. White, Claude Messier, and Geoffrey D. Carr

Department of Psychology
McGill University
1205 Dr. Penfield Avenue
Montreal, Quebec, Canada H3A 1B1


Abstract
This paper examines the use of conditioning methods to measure the organizing influence on behavior of natural reinforcers and of the reinforcing drug amphetamine. The problems associated with the objective measurement of reward and aversion are discussed and it is suggested that the tendency to approach or to withdraw from stimuli associated with reinforcers canrom stimuli associated with reinforcers can provide an objective index of the rewarding or aversive value of these reinforcers. However, reinforcing drugs do not provide an external reference point; consequently, researchers have used conditioning methods that promote the association of external stimuli with the internal effect of the drug. The advantages of these associative conditioning methods and the problems of interpretation associated with them are discussed. The fact that some reinforcing drugs also have the separate property of improving memory is presented as a special interpretative problem. This discussion of the measurement of the organizing influence of reinforcers on behavior is illustrated by experiments using three different associative conditioning methods: taste conditioning and two place conditioning methods (preference and runway). These methods were used to assess the organizing influence of peripheral and central d-amphetamine, sucrose, and saccharin solutions.

 

Introduction

Reinforcement is the process that occurs in the nervous system when contact with certain stimulus events (called reinforcers) produces a change in behavior. The administration of certain drugs (called reinforcing drugs) often produces behavioral changes that resemble those produced by naturally reinforcing events. This similarity of effect has lenforcing events. This similarity of effect has led to the view that the influences on behavior of natural reinforcers and of reinforcing drugs can be studied using similar assumptions and techniques. Our approach involves the parallel analysis of the effect of these two types of events on behavior. This approach may help to reveal the neural basis of the influence on behavior exerted by both natural reinforcers and by reinforcing drugs.

It is generally agreed that reinforcers can have two different qualities. Although there is not agreement on terminology, these qualities have been described as positive and negative or as rewarding and punishing. The corresponding reinforcement processes initiated by these events are referred to as reward and aversion. The fact that most workers use the terms reinforcement and reward or aversion and punishment interchangeably suggests that these qualities of reinforcement form the basis of thinking about the process. A discussion of the reinforcement process can therefore begin with a consideration of these qualities.

Present notions of reward and aversion emerge from a long line of philosophical and psychological thought. The pleasure principle—the idea that individuals behave so as to maximize pleasure and minimize pain—is present in the writings of the Epicureans, the Hedonists, and the Freudians. The theory of evolution can be used to predict that behaviors promoting survival are associated with pleasung survival are associated with pleasure and that behaviors impeding survival are associated with pain. However, these teleological views clearly relate to the affective experience of individuals rather than to the objective measurement of the influence of events on behavior. The psychologist P.T. Young (1959, 1961, 1966) made an important contribution to thinking on this issue because he recognized both the existence of affective experience and the need to study the behavior associated with it in an objective manner.

Contributions of P. T. Young

Young developed the preference technique as a measure of the affective properties of environmental stimuli. He argued that the best measure of affect consists of brief exposures to two stimuli, followed by a test to see which of the two is preferred. He stressed that drawing conclusions about the affective value of stimuli requires that the experimenter observe the development of a preference and that this method measures only relative preference.

In one series of experiments, Young and Falk (1956) measured preference for sodium chloride solutions. They observed that preference for these solutions increased with concentration up to a certain point but decreased at higher concentrations—a conclusion confirmed electrophysiologicallyion confirmed electrophysiologically by Pfaffman (1960). Young and Christensen (1962) showed that preference for a sucrose solution is increased by adding a low concentration of salt and that preference for the same sucrose solution is decreased by adding a higher concentration of salt. Therefore, the affective properties of stimuli summate algebraically to determine the final level of preference. Algebraic summation of lateral hypothalamic self-stimulation (reward) and lithium chloride injections (aversion) has more recently been demonstrated by Ettenberg, Sgro, and White (1980).

One property of the affective states produced by stimuli and implied by the notion of algebraic summation is their sign: They can be rewarding or aversive. Reward and aversion exist on an affective continuum (Young, 1959), and, at any moment in time, an animal occupies one and only one position on the affective continuum with respect to a particular stimulus. The position may be rewarding, neutral, or aversive, and it may be the outcome of the summation of several different processes with different affective signs relating to the same or different stimuli. In a given environment the presence of one or more reinforcing stimuli therefore serves to organize an animal’s behavior by influencing "neurobehavioral patterns" that serve to "orient the organism towards or against the stimulus object" (Young, 1961). Four issues of relevance to the problem of measuri of relevance to the problem of measuring the effects of drugs on behavior are raised by this brief summary of Young’s views.

Neurobehavioral Patterns

Like other psychologists of his time (e.g., Hebb, 1949; Hull, 1951), Young understood that the behaviors he observed were mediated by events in the nervous system but was unable to discuss these events because little information about them was available. However, his approach was conducive to the eventual study and elucidation of these neural events because of his willingness to consider the existence of a (intervening) variable such as affect. With the techniques for studying the nervous system available to today’s behavioral neuroscientist, the prospect of describing Young’s organizing neurobehavioral patterns and substituting them for the concept of affect becomes real.

Pharmacological techniques are among those that can be of value in locating and studying the neural substrates of behavioral organization. Some reinforcing drugs may act directly on these substrates. Others may act indirectly on central or peripheral systems which influence these substrates. It is also possible for a drug to act on more than one substrate. To study these possibilities we require an objective method of measuring the affective influence of drugs on behavior.

Objective Measurement of Reward and Aversion

A preference for one of two stimuli implies either that the affect produced by the preferred stimulus is relatively rewarding or that the alternative choice produces relative aversion. Young pointed out that the actual observation in this situation is a tendency for an animal to orient towards or away from a reinforcing stimulus. It seems clear that conclusions about the affective properties of stimuli are in fact based on observation of the orientation and approach or withdrawal behaviors they produce. The tendency to orient towards, to approach, and to maintain contact with a stimulus is interpreted as evidence of a rewarding process. The tendency to orient away from a stimulus and to withdraw from it is taken as evidence of aversion. The preference method gives us an operational definition of reward and aversion in terms of approach and withdrawal, thereby allowing their objective study.

The fact that certain stimuli produce approach and others produce withdrawal must surely be among the most elementary behavioral observations that can be made. Schneirla (1959; Maier & Schneirla, 1964) has emphasized that these two behavioral tendencies are properties of the simplest living organisms (including plants and the single-celled amoeba) and that they are present in all animals including humans. Herrick (1948) describes how whole-body movements towards or away from environmental stimuli are controlled by undifferentiated ne are controlled by undifferentiated nervous systems of primitive organisms and how in higher animals there is a parallel increase in the specificity of the behavioral response and the differentiation of the neural substrate controlling it.

In measuring approach and withdrawal tendencies, we study elementary properties of behavior mediated by neural substrates which, in a more or less differentiated form, are present in all living organisms and which act to organize behavior. The concepts of affect and reward or aversion that were useful to Young as substitutes for knowledge about the neural substrate of approach and withdrawal can now be put into their proper perspective as manifestations of individual experience. These manifestations are irrelevant to the objective study of affect because they are accessible only by introspection. An equally intractable question is whether or not affective states exist in the absence of behaviors such as approach and withdrawal. We can, however, answer questions about the influence of natural and pharmacological events on the neural substrates of approach and withdrawal by quantifying these behaviors.

Given that this is what we can measure, we should be careful to state what we mean by the terms reward and aversion. Reward is activity in the brain that promotes approach and maintenance of contact, and aversion is activity in the brain that promotes withdrawal. One of our major goals is, of coural. One of our major goals is, of course, to state precisely what is meant by "activity in the brain." The use of pharmacological techniques is a major tool in the effort to arrive at this definition.

It should also be noted that defining affect in terms of approach and withdrawal means that the study of these phenomena is no longer confined to the use of preference methods. Other methods of measuring the same two classes of behavior could, in principle, provide equally valid information about the effects of reinforcers on the neural substrates which organize behavior. In a later section we describe our efforts to develop a measure of approach using a runway.

The Role of Learned Associations

External stimuli play an essential role in the development and detection of approach and withdrawal. These behaviors can exist only in the presence of some external stimulus to which they can be referred by both the animal and the experimenter. In the case of experiments using food, the sight, smell, and taste of the stimulus provide the external reference point required for either of the behaviors to develop. As the animal consumes a sweet food, for example, the neural substrate mediating approach and maintenance of contact becomes activated, and the discriminable environmental stimuli become associated with this activated state. If this learned association is retained (and this memory may be facilitated by thand this memory may be facilitated by the reinforcer), the animal will exhibit the same behavior when it next encounters the same situation, leading to increased consumption of the sweet food.

Other events which do not naturally provide external stimulus reference points may also activate the neural substrates of approach or withdrawal (The question of whether or not this occurs is one that can be answered empirically.), but these behaviors cannot develop in the absence of such external stimuli. A classic instance of this problem was the discovery of the so-called "medicine effect" by Harris, Clay, Hargreaves, and Ward (1933). These workers showed that when rats deficient in vitamin B1 were offered a choice among a number of foods, they quickly learned to prefer the taste of the only one that contained B1 if the taste of that food was discriminable from the tastes of the alternate foods offered. If the vitamin was present in one of several foods with the same taste, the animals failed to exhibit a preference for it. Thus, in the absence of an external stimulus, the behavioral effects of replacement therapy were neither expressed nor measurable. In the presence of such a reference point, the animals learned a tendency to approach and maintain contact with the discriminable B1-containing food, and this tendency was observed as increased consumption of that food.

The medicine effect clearly illustrates a problem of measuring the organiates a problem of measuring the organizing effect of reinforcing drugs on behavior. Regardless of how or where any drug may interact with the nervous system, it is clear that it cannot provide an external reference point. Therefore, neither approach nor withdrawal will be expressed or detected unless the drug is administered in an experimental situation which includes discriminable stimuli and which promotes the formation of an association between those stimuli and any effect the drug may have on the neural substrates of approach or withdrawal.

Successful techniques for measuring the rewarding or aversive properties of drugs have, in fact, used this method. The conditioned taste aversion (CTA) method (Goudie, 1979; Revusky & Bedarf, 1967) promotes the formation of an association between the organizing effects of drugs and novel tastes. Conditioned place (Kumar, 1972) and runway (White, Sklar, & Amit, 1977) methods promote the formation of associations between the effects of drugs and the visual, olfactory, and tactile stimuli that constitute a given experimental environment. Such associations are also formed in self-administration paradigms. Providing a discriminative stimulus signaling delivery of the reinforcer accelerates acquisition of bar-pressing responses for intragastric food (Holman, 1969) and for intravenous amphetamine (Thompson, Bigelow, & Pickens, 1971).

The use of associative conditioning methods to mea associative conditioning methods to measure the organizing influence of drugs on behavior has at least one advantage. During training the influence of the drug is paired with neutral stimuli, but during testing the animal’s behavior is free from any direct influence the drug may have on behavior because the drug is not administered. This is particularly important in the case of drugs thought to affect motor behavior (e.g., pimozide: Ettenberg, Cinsavitch, & White, 1979). It should be kept in mind, however, that conditioned physiological changes may occur on the test day in the absence of the drug (e.g., the temperature change produced by morphine; Eikelboom & Stewart, 1979) and that such effects could influence behavior directly.

Dual Action of Reinforcers

The fact that a learning process is required to measure the approach and withdrawal behaviors produced by reinforcing drugs necessitates a consideration of the role of reinforcers in learning. Reinforcers initiate two processes that are relevant here. The first process is the influence of the stimulus properties of reinforcers on the neural substrates of approach and withdrawal. As described in the previous section, some neutral stimulus becomes associated with this influence. The second process is the influence of reinforcers on an animal’s tendency to remember this association. Young (1940) may have been the first to point out that althougheen the first to point out that although the stimulus properties of reinforcers serve to organize behavior, they have no influence on an animal’s tendency to remember this organizing influence. However, it seems clear that some nonstimulus property of reinforcers can initiate a memory improving process.

In a series of experiments, Major and White (1978) and Coulombe and White (1980) showed that electrical self-stimulation of certain brain regions can improve memory independently of its rewarding properties. More recently, Messier and White (1984) used a conditioned taste preference (CTP) paradigm to identify solutions of sucrose and of saccharin with equivalent organizing influences on behavior (i.e., pairing a flavored solution with each of the sweet substances produced equal preferences for the paired taste). Subsequent experiments in which the animals drank these same solutions after training on a conditioned emotional response (CER) task showed that sucrose improved memory for the CER but that saccharin had no such effect. Subcutaneous injections of glucose also improved memory. These data show that although the organizing influence of the solutions depended on their stimulus properties, the memory improving action of sucrose must have been the result of some postingestional effect. It should be noted that this memory improving action of reinforcers is not essential for retention; it merely facilitates storage if it is present.ly facilitates storage if it is present.

The distinction between the organizing and the memory-improving processes initiated by reinforcers is important for two reasons. First, evidence exists that some reinforcing drugs influence memory independently of their organizing influences (amphetamine: Carr & White, 1984; Doty & Doty, 1966; Krivanek & McGaugh, 1969; morphine: White, Major, & Siegal, 1978). Second, as previously discussed, techniques for measuring the organizing action of drugs rely on the formation of learned associations which must be remembered.

Problems of Interpretation with Conditioning Methods

Associative conditioning methods involving taste or place are used to obtain information about the tendency of reinforcing events, including drugs, to organize behavior by producing approach or withdrawal. Inferences about the sign and amplitude of the organizing properties of reinforcers are made from observation of animals’ responses to the conditioned stimuli. However, the interpretation of responses to conditioned stimuli as measures of the organizing properties of reinforcers is constrained by certain features of the associative conditioning process itself.

As already discussed, two processes are involved when an associative conditioning procedure causes a change in behavior. First, the animal must experience the associative relationship between a neutral stimulus and thehip between a neutral stimulus and the stimulus properties of the reinforcer. Second, the animal must remember this association. Both of these processes present interpretative problems.

Associative Bias

It is well-known that stimuli and responses differ in their associability (Garcia & Koelling, 1966; Glickman, 1973; Moore, 1973; Seligman, 1970; Shettleworth, 1973), a phenomenon that can be referred to as associative bias. According to this principle, variability of observed responses to conditioned stimuli in taste or in place conditioning experiments may be due to differences in the tendency of the organizing properties of a reinforcer to become associated with a given conditioned stimulus rather than to variability in the amplitudes of the organizing influences themselves. Another problem is the possibility that a drug may act at more than one site in the brain and that the behavioral influence of these different actions can be expected to summate algebraically, obscuring the fact that the observed behavior is the result of more than a single action.

Data already available for the drug amphetamine provide a good example of these problems. Peripheral administration of this drug in a taste conditioning paradigm gives evidence of aversion (Carey, 1973), but administration of similar doses in a place conditioning paradigm gives evidence of reward (Reicher & Holman, 1977). The considerations under discussion). The considerations under discussion suggest the hypothesis that amphetamine may exert organizing influences with opposite signs by acting on more than one neural substrate. One of these influences is a direct or indirect activation of the substrate of withdrawal, and this activation may have an associative bias for taste stimuli. The other influence is activation of the neural substrate of approach, and this action of the drug may have an associative bias for place stimuli. In the following sections we describe our investigations of this hypothesis.

Memory of the Association

Since some drugs have a memory improving effect as well as an organizing influence on behavior, variability in observed responses to the conditioned stimuli could be due to variability in either process. It is possible to imagine two substances with equally strong organizing influences on behavior but with different memory improving properties. In such a case clear approach or withdrawal relative to the conditioned stimulus may be observed for the substance that promotes the memory of the association between its own organizing properties and the stimulus, but much weaker responses or no responses at all may be observed for the substance that does not promote retention of this memory. For example, White and Carr (1985) found that although conditioned place preferences are observed when sucrose solutions are used as the reinforcers, equally re are used as the reinforcers, equally rewarding saccharin solutions have no such effect. When postpairing, memory-improving treatments (injections of glucose or amphetamine) followed the saccharin- and control-environment pairings preferences were observed, confirming the role of memory improvement in this situation.

The distinction between the organizing and the memory-improving effects of drugs must be stressed. In particular effects on memory cannot change the sign of an organizing influence. Even if a memory effect distorts the appearance of an organizing effect, such distortion cannot include changing approach into withdrawal or vice versa. Therefore, a detected behavioral tendency is a reliable index of a neural process. The problems of interpretation arise in the absence of an observed effect, or in trying to compare the organizing properties of different reinforcers, or in comparing the same reinforcer using different methods.

In our laboratory we have investigated the effects of "natural" reinforcers (cases where the nature of the organizing influence is generally accepted) and of reinforcing drugs on approach and withdrawal using taste conditioning and two types of place conditioning methods. We have tested the ability of each method to detect rewarding and aversive influences of natural reinforcers. We have also studied the effects of amphetamine on behavior in each of the paradigms. These experiments provide informatioms. These experiments provide information on the usefulness of each of the methods for measuring the organizing properties of a reinforcing drug. They also form an initial test of the hypothesis that amphetamine has more than one organizing influence on behavior by acting at more than one site in the brain.

Taste Conditioning Method

The use of taste conditioning methods to measure the organizing properties of reinforcing stimuli rests on the discovery of a phenomenon that has come to be known as the conditioned taste aversion (CTA: Garcia, Kimmeldorf, & Hunt, 1957; Richter, 1945, 1953). There is a large literature demonstrating that the pairing of a variety of taste stimuli with a number of different treatments causes animals to withdraw from the paired taste on future occasions (Garcia, Hawkins, & Rusiniak, 1974; Revusky & Garcia, 1970). In most cases there was already reason to believe that the treatments producing these effects were aversive, and the demonstration that these reinforcers produced CTAs served to confirm this information and to validate the method. However, the demonstration that CTAs are produced by certain self-administered drugs (e.g., morphine: Cappell, LeBlanc, & Endrenyi, 1973; Jacquet, 1973; and amphetamine: Carey, 1973) was regarded as paradoxical because the fact that they are self-administered suggests that they are rewarding, not aversivgests that they are rewarding, not aversive.

Natural Reinforcers

There have also been a few demonstrations that taste conditioning methods can be used to measure the rewarding effects of various reinforcers. The medicine effect (Harris et al., 1933) already described was the first example of this phenomenon. More recently, it has been shown that pairing a session of drinking a novel tasting solution with a sweetener (Holman, 1975) or with a session of electrical self-stimulation of the brain (Ettenberg & White, 1978) resulted in a subsequent preference for the solution with the novel flavor. Since we wished to validate the ability of this method to measure reward as well as aversion, we paired the drinking of flavored solutions with the sweet taste of sucrose and saccharin to determine if the approach tendencies one would expect these rewarding events to produce could be detected by this method.

Rats were presented with two flavored solutions simultaneously over a two day period: For each rat sucrose or saccharin was mixed with one of the solutions, resulting in the pairing of a novel flavor with a sweet taste. When offered a choice between the two flavors with no sweeteners, the rats drank significantly more of the solutions that had been paired with all concentrations of sucrose and saccharin (see Figure 1). Since each of the flavors was paired for half of the animals in each group, this resultf the animals in each group, this result cannot be attributed to preferences for the flavors themselves and must therefore be attributed to the formation and retention of an association between the conditioned taste stimuli and the rewarding effect of the sweet substances.

These results show that the conditioned taste method can be used to detect the organizing properties of at least some reinforcers that tend to produce approach and maintenance of contact. The facts that both sucrose and saccharin produced approximately equal shifts in responding to the conditioned taste stimuli and that saccharin has no reliable postingestional effect (Steffens, 1969a, 1969b) suggest that the tastes of the two reinforcers were the sources of their organizing influences. This conclusion is consistent with a previous suggestion of Holman (1975).

Amphetamine

Taking this confirmation of the ability of the taste conditioning method to detect the rewarding effects of natural reinforcers together with the data on the CTA which demonstrate its ability to detect a drug’s aversive effects as a validation of the method, we applied it to the study of the organizing properties of amphetamine. In our first experiment we replicated previous findings (Carey, 1973) that pairing of drinking a flavored solution with an injection of the drug produces withdrawal from the conditioned taste stimulus, suggesting aversion (see Figure 2). Ts, suggesting aversion (see Figure 2). The conclusion that the data for the amphetamine-paired animals represent a genuine conditioned withdrawal response to the taste is supported by the fact that the animals in the unpaired group, in which plain water was paired with a drug injection, consumed more of the flavored solution on test day than did the rats in the paired group.

Our next step was to use this taste conditioning method to determine if the site of amphetamine’s aversive action in the brain could be detected by injecting the drug directly into local brain sites. Wagner, Foltin, Seiden, and Schuster (1981) showed that the CTA produced by systemic injections of amphetamine is attenuated by (relatively) selective depletions of brain dopamine. Since a major pharmacological action of amphetamine in the CNS is a facilitation of endogenous dopaminergic activity (Fuxe & Ungerstedt, 1970; Sulser & Saunders-Bush, 1971), this finding suggests that dopaminergic neurotransmission may be the basis of the aversive organizing influence of amphetamine. Accordingly, we decided to inject the drug into three of the major forebrain areas known to contain dopamine: nucleus accumbens, caudate nucleus, and amygdala. There is also evidence (Berger, Wise, & Stein, 1972; McGlone, Ritter, & Kelley, 1980) that the CTAs produced by various toxins (e.g., lithium chloride, although not amphetamine) are abolished by thermal lesions of area p abolished by thermal lesions of area postrema. We also selected the region around this structure as an injection site.
 

 
Effect of natural reinforcers on taste conditioning
Figure 1: Effect of natural reinforcers on taste conditioning. Each bar shows consumption of paired solutions (together with standard errors and numbers of subjects) during 30-minute preference test following 48 hours of experience with almond- and chocolate-flavored solutions. During the 48-hour pairing, one of the solutions (almond for half of the subjects and chocolate for the other half) available to the rats in each group was adulterated with sucrose or saccharin. During the 30-minute test period the flavored solutions were unadulterated. Consumption of paired solution was significantly higher than consumption of unpaired solution for all groups [F (1,61) = 32.09, p < 0.01].
 

Pairing a session of drinking flavored solutions with direct microinjections of amphetamine into nucleus accumbens, caudate nucleus, or amygdala had no effect on the animals’ subsequent behavior towards the paired tastes (see Figure 3). As discussed above, however, this result must be treated with caution. The absence of an effect may hesult must be treated with caution. The absence of an effect may have been caused by the lack of an organizing influence of amphetamine at these brain sites, by the inability of the animals to associate the taste stimuli with this influence, or by their inability to remember the association if it was formed. As also shown in Figure 3, pairing of a taste stimulus with microinjection of amphetamine into the region around the area postrema caused a reduction in consumption of the solution with the paired taste, suggesting that the drug acted at this site in the brain to initiate a withdrawal response.
 

 
Effect of amphetamine on taste conditioning
Figure 2: Effect of amphetamine on taste conditioning. Each bar shows the mean amount of solution with paired taste consumed during a 15-minute test 24 hours after pairing. On pairing day the rats in the first three groups shown all drank a solution of instant decaffeinated coffee and almond extract in water for 10 minutes. Following this the rats in the untreated group received no treatment, the rats in the saline group received subcutaneous injections of physiological saline, and the rats in the amphetamine group received subcutaneous injections of 2 mg/kg d-amphetamine sulphate in saline. The rats in the amphetamine unpaine sulphate in saline. The rats in the amphetamine unpaired group drank water and then received the same injection of amphetamine. Each bar shows the standard error of the mean and the number of subjects. The amount of coffee consumed by the rats in the amphetamine groups was significantly lower than the amounts consumed by the rats in the other groups [F (3,53) = 20.17, p < 0.001].
 

These data suggest that the aversive action of amphetamine that is observed when taste stimuli are paired with peripheral injections may occur because of an action of the drug in the region around the area postrema. We suggest that the site of action is in the region of the area postrema but not restricted to the structure itself because lesions restricted to the structure do not block the aversive action of amphetamine observed in a taste conditioning paradigm (Berger, Wise, & Stein, 1972). This finding does not, of course, preclude the possibility that amphetamine may also have aversive or rewarding influences on behavior by acting at other brain sites.
 

 
Effect of local microinjections of amphetamine on taste conditioning
Figure 3: Effect of local microinjections of amphetamine on taste conditioning. Cannulae wermicroinjections of amphetamine on taste conditioning. Cannulae were aimed at the following Pellegrino, Pellegrino, and Cushman (1979) coordinates, and subsequent histological examination confirmed that the tips were clustered around these points (all referred to stereotaxic zero): Caudate 7.8 mm anterior, 4.0 mm lateral, 1.0 mm above; accumbens, 9.4, 1.5, 0.0 (cannulae angled 20 degrees to avoid ventricle); central nucleus of amygdala 6.2, 4.0, -2.0; area postrema -4.5, 0.0, -7.0. Data for rats in the untreated, accumbens, and caudate groups are shown in A. These animals experienced a single pairing of a coffee-almond flavored solution followed by an injection of 10 mg d-amphetamine sulphate in 0.5 mL physiological saline or saline alone. The data shown are for a 30-minute drinking period with only the flavored solution available. Data for the rats in the amygdala and area postrema groups are presented in B. These rats experienced one or three pairings of a maple-sucrose solution followed by 20 mg amphetamine in distilled water or an isomotic injection of saline solution. The data shown are for a 30-minute test with the flavored solution and water available. All injections were administered over 30 seconds. The numbers of subjects in each group and the standard errors of the means are shown on each bar. The only significant effects are for the area postrema injections wi for the area postrema injections with one pairing [t (12) = 3.48, p < 0.005] and three pairings [t (12) = 4.82, p < 0.001].
 

Summary

It is well known that the taste conditioning paradigm can detect the aversive consequences of various toxic substances by producing withdrawal from the conditioned taste stimuli. A smaller amount of data, including those presented here, suggest that, in some circumstances at least, the technique can also detect the rewarding effects of reinforcing events by producing approach and maintenance of contact with the conditioned taste stimuli. In our attempts to use this method to study the organizing influence on behavior of amphetamine, we replicated previous findings that the technique detects an aversive action of peripherally administered amphetamine and showed that a central microinjection of the drug into the region of area postrema produces a similar effect. No effects of microinjections into caudate nucleus, nucleus accumbens, or amygdala were detected. These data suggest that amphetamine may exert at least part of its aversive organizing influence on behavior through an action on neural tissue in the region of area postrema. Further experiments will be necessary to confirm this suggestion.

Place Conditioning: Preference Method

A version of the place preference method was first used to study the behavioral effects of morphine by Beach (1957). More recently, other versions of the method were used by Kumar (1972), by Rossi and Reid (1976), and by Mucha, van der Kooy, O’Shaughnessy and Bucenieks (1982). It is based on the idea that when animals experience the organizing influence of a reinforcer in the presence of the constellation of stimuli constituting a distinctive environment, they learn an association between the stimuli and the organizing influence. On future occasions these learned associations lead the animals to approach and maintain contact with or to withdraw from the conditioned stimuli. The technique has been used to detect the rewarding effect of food (Spyraki, Fibiger, & Phillips, 1982a) and the aversive effect of lithium chloride injections (Ettenberg, van der Kooy, LeMoal, Koob, & Bloom, 1983; Mucha et al., 1982). Rewarding effects of morphine (Mucha et al., 1982; Rossi & Reid, 1976) and of amphetamine (Reicher & Holman, 1977; Spyraki, Fibiger, & Phillips, 1982b) have also been detected with this method.

In our work with the place preference technique, we use the apparatus illustrated in Figure 4. On the first day of our experiments, the rats are allowed to explore the apparatus freely for 10 minutes. On each of the following 12 days, each rat is confined in one of the two large compartmented in one of the two large compartments and experiences a reinforcing or a control event. In each group of each experiment, half of the rats experience the reinforcer in compartment "A" on the even numbered days and the control treatment in compartment "B" on the odd numbered days. The other half of the rats experience the control event in compartment "A" and the reinforcer in compartment "B." On Day 14 each rat is placed into compartment "C" and allowed to move freely in the apparatus for 20 minutes. The amount of time each rat chooses to spend in each of the two large compartments is measured. If the rats spend significantly more time in the presence of the reinforcer-paired stimuli than with the control-paired stimuli, we conclude that the reinforcer produced a tendency to approach and to maintain contact. If the rats in a group choose to spend significantly less time in the presence of the reinforcer-paired stimuli than with the control-paired stimuli, we conclude that the reinforcer produced a tendency to withdraw. Pilot experiments have shown that rats run through this procedure with no reinforcers exhibit approximately equal preferences for the two large compartments.

Natural Reinforcers

We began our work with this method by attempting to verify its ability to detect conditioned approach and withdrawal produced by known rewarding and aversive events. Using the same three concentrations of sucrog the same three concentrations of sucrose we had used to test the taste conditioning method, we observed a relationship between concentration of sucrose and amount of time spent on the paired side but a clear preference for the paired side only when the 20% sucrose solution was the reinforcer (see Figure 5). By comparison, all three of these concentrations of sucrose produced significant preferences in our taste conditioning experiment, and the lowest preference was observed with the 20% solution (see Figure 1). The difference in the effect of the 20% sucrose solution can be explained by the fact that, unlike the rats in the taste experiment, the rats in the place experiment were food-deprived, a condition that is known to increase the preferred concentration of sucrose (Collier & Bolles, 1968).
 

 
Plan view of the place conditioning apparatus
Figure 4: Plan view of the place conditioning apparatus. Compartments A and B (45 x 45 x 30 cm) have wooden walls and tops and Plexiglas fronts. The distinguishing stimulus features of the two environments are shown on the figure. Compartment C is constructed entirely of wood. The dotted line represents a removable wooden partition.
 
 

It is also worth noting that the present place conditioning method detected the rewarding effect of sucrose after only six 30-minute pairings, while 48 hours of continuous pairing in our experiment and ten 60-minute pairings in Holman’s (1975) experiment were required to detect reward using the taste conditioning method. Although the procedures of the various experiments do not permit precise comparisons, the suggestion that the place method may be a more sensitive measure of reward than the taste method is worth further study.

Figure 5 also shows our attempt to detect the influence of an aversive event in this apparatus, using an injection of a moderate dose of lithium chloride as the reinforcer. Our failure to detect a significant effect of this dose of lithium is in contrast to the significant aversion we observed with the same dose in using the taste conditioning method (see Figure 5, inset). Using a higher dose of lithium (60 mg/kg), however, we have observed significant aversion using our place conditioning method, confirming findings from other laboratories (Ettenberg et al., 1983; Mucha et al., 1982). These findings suggest that the taste method may be a more sensitive detector of aversion than the place method.
 

 
Effect of natural reinforcers in place conditioning
Figure 5: Effect of natural reinforcers in place conditioning. All rats in the sucrose groups were on a 22 hour food deprivation schedule. All rats were allowed to drink their reinforcing solution freely while on their paired sides of the apparatus and were given no treatment on their control sides. Each bar shows the standard error of the mean and the number of subjects in each group. The 20% sucrose reinforcer produced a significant preference [t (6) = 2.34, p < 0.05]. The rats in the lithium chloride group were given an intraperitoneal injection of 32 mg/kg (0.75 mEq/kg) lithium chloride in distilled water (15 mg/cc) before being placed into their paired sides and an injection of an equivalent volume of physiological saline before being placed into their control sides. There was no significant effect of the lithium treatment. The inset shows the significant aversion [t (11) = 6.89, p < 0.01] produced by a single pairing of a maple-flavored solution with the same dose of lithium in a taste conditioning experiment. The animals in this experiment also experienced pairings of a saccharin-flavored solution with a saline injection in random order with respect to the maple-lithium pairing. Data are for a 30-minute test with appropriate flavored solutions available.
 
 

Amphetamine

Our next step was to replicate and extend previous findings that the place preference technique can detect a rewarding effect of peripherally administered amphetamine. Using four different doses of amphetamine as reinforcers, we observed significant preferences for the paired side at the three higher doses and a significant dose-response measure of the tendency of amphetamine to produce approach and maintenance of contact (see Figure 6).

As has been noted, the finding that amphetamine produces evidence of reward in this paradigm is in contrast to the evidence of aversion the same drug gives in the taste conditioning paradigm. To continue our investigation of the hypothesis that these two effects are due to actions of the drug at different brain sites, we tested the effects of intracerebral microinjections of amphetamine, aimed at the same four sites tested with the taste method, using the place conditioning method. A significant preference for the paired side was observed only for rats that experienced injections into nucleus accumbens (see Figure 7). This finding suggests that peripherally injected amphetamine may produce its rewarding effect by acting at this site, although it does not, once again, eliminate the possibility that the drug may also have a similar action at other sites. Given the fact that the primary effect of amphetaminfact that the primary effect of amphetamine in nucleus accumbens is release of endogenous dopamine, this finding suggests that dopaminergic function in nucleus accumbens may act to produce approach and maintenance of contact with external stimuli. This conclusion is consistent with results reported by other workers: Self-administration of amphetamine (Lyness, Friedle, & Moore, 1979) and of cocaine (Roberts, Koob, Klonoff, & Fibiger, 1980) and the conditioned place preference produced by amphetamine (Spyraki, Fibiger, & Phillips, 1982b, 1982c) are both blocked by dopamine-selective lesions of nucleus accumbens.
 

 
Effect of peripheral amphetamine on place conditioning
Figure 6: Effect of peripherally injected amphetamine on place conditioning. Each rat was injected subcutaneously with one of the indicated doses of amphetamine (in 1 cc/kg physiological saline) before being placed into its paired side and with an equivalent volume of saline before being placed into its control side. Each bar shows the standard error of the mean and the number of subjects. Significant preferences were observed at 0.5 [t (7) = 2.13, p < 0.05], 1.0 [t (7) = 3.74, p < 0.005], and 2.0 [t (8) = 4.07, p < 0.005] mg/kg. In addition, a significant do4.07, p < 0.005] mg/kg. In addition, a significant dose-response relationship (r = 0.61, p < 0.001) was found for the four doses tested.
 

 
 
Effect of intracerebral microinjection of amphetamine on place conditioning
Figure 7: Effect of intracerebral microinjection of amphetamine on place conditioning. All injection parameters were the same as those used in the taste conditioning experiments (except that the dose in the amygdala groups was 10 mg). Rats tested in the amphetamine-saline condition received intracerebral injections of amphetamine before being placed into their paired sides of the place apparatus and the same volume of isotonic saline solution into the same brain areas before being placed into their control sides. Rats tested in the amphetamine-no treatment condition were injected with amphetamine before being placed into their paired sides and received no treatment before being placed into their control sides. Each bar shows the standard error of the mean and the number of subjects. Significant preferences for the paired sides were observed for both nucleus accumbens groups (saline control: t (16) = 2.01, p < 0.05; no treatment control: t (16) = 3.25, p < 0..01, p < 0.05; no treatment control: t (16) = 3.25, p < 0.01).
 

Injections of amphetamine into caudate nucleus, amygdala, or the region of area postrema had no influence on the animal’s behavior. Once again these latter results must be interpreted with caution. These negative data may mean that the injections produced no organizing effect on behavior, or they may mean that the animals failed to acquire or to remember associations between the environmental stimuli and organizing effects of amphetamine that may have been present.

Associative Bias in the Place and Taste Methods

Our earlier failure to observe an effect of injections of amphetamine into nucleus accumbens using the taste conditioning method (see Figure 3) is in contrast to the evidence of reward detected using place conditioning. A possible cause of this difference is the fact that our place method includes six environment reinforcer pairings while only a single pairing was used in the taste experiment. Accordingly, we repeated the taste conditioning experiment, pairing eight sessions of drinking a flavored solution with nucleus accumbens injections of amphetamine. All injection parameters were the same as in the taste and place experiments already described, and the testing included a free choice with water. Nonetheless, we still failed to observe any significant shift in the animals’ resto observe any significant shift in the animals’ responses to the conditioned taste stimulus.

These data support the conclusion that injections of amphetamine into nucleus accumbens have no effect in the taste method but give evidence of reward in the place method. Conversely, injections into the region of area postrema give evidence of aversion in the taste method (one pairing) but have no effect in the place method (six pairings). It is, of course, possible that higher or lower doses of amphetamine might produce an effect where none was observed in these experiments. Nevertheless, when comparing the characteristics of different methods of measuring the effects of drugs, data for the same dose in both situations are what is required to make such comparisons.

It therefore appears that amphetamine may have at least two independent organizing influences with opposite signs at two different brain sites. The drug’s rewarding action in nucleus accumbens is biased towards forming associations with place stimuli. The drug’s aversive action in area postrema is biased towards forming associations with taste stimuli. None of this precludes the possibility that amphetamine may also have other actions at other brain sites.

These conclusions on associative bias with amphetamine are in line with the data for sucrose and for lithium, suggesting that the place method may be a more sensitive detector of reward and that the taste method may be a more seand that the taste method may be a more sensitive detector of aversion. Considering the data for amphetamine and natural reinforcers together leads to the suggestion that organizing influences producing approach and maintenance of contact are more easily associable with the environmental stimuli in a place conditioning apparatus and that organizing influences producing withdrawal are more easily associable with taste stimuli.

Summary

The place preference technique appears to be an adequate measure of both the rewarding and the aversive influences on behavior of natural reinforcers. However, comparisons of the effects of the same concentrations of sucrose and of the same doses of lithium in the place and taste conditioning methods suggest that the former may be a somewhat more sensitive measure of reward than the latter. Our demonstration of a dose-response relationship for peripherally injected amphetamine suggests that the place conditioning method is a sensitive detector of the rewarding effects of this drug. Intracerebral microinjections of amphetamine at four different sites revealed a preference only with nucleus accumbens injections. Taken together with the data on intracerebral injections using the taste method, these findings suggest that amphetamine has at least two behaviorally important sites of action: a rewarding effect in nucleus accumbens and an aversive effect in area postrema. The assumpte effect in area postrema. The assumption of associative bias can provide an explanation of the data on the differences in the abilities of the two methods to detect rewarding and aversive organizing influences on behavior.

Place Conditioning: Runway Method

The two techniques for studying the organizational influences of reinforcers discussed in the previous sections measure approach and withdrawal indirectly: In one case the amount consumed of a substance flavored with the conditioned taste stimulus is measured, and in the other case the amount of time spent in the presence of the conditioned environmental stimuli is measured. An alternative type of measure commonly used in experimental psychology to measure the organizing properties of food and water makes use of a runway. In this case approach responses are directly observed and can be quantified in terms of the animals’ running speeds.

Although this technique has not been widely used to measure the organizing influence of drug reinforcers on behavior, two recent studies suggest that two recent studies suggest that it may be a valuable tool. White, Sklar, and Amit (1977) showed that rats’ running speeds increased from day to day when they had been given one trial per day with an injection of morphine while remaining in the goal box for an hour after each trial. Increases in running speed can be interpreted as increases in the intensity of the animals’ tendency to approach the goal box, suggesting that morphine has a rewarding influence on behavior. These findings are consistent with the results of place conditioning experiments using this drug. Distinctively flavored food was available in the goal box, and the animals were allowed to eat for a few minutes before receiving their drug injections. The amount of food consumed decreased from day tocreased from day to day while, on the same trials, the animals were showing evidence of reward. The decrease in consumption, which is consistent with the results of other taste conditioning experiments with morphine, suggests that the drug also produced aversion. Reicher and Holman (1977) reported similar results for amphetamine using a version of the place conditioning method.

These findings can be interpreted in terms of associative bias. In agreement with data presented in the previous sections, it is possible that the rewarding effect of the drugs is biased towards the formation of associations with the place stimuli in the goal box and that the aversive effect of the drugs is biased towards the formation of associations with the taste stimulih the taste stimuli also present there. Whether or not this explanation is correct, the fact that this method appears to detect both reward and aversion simultaneously would seem to make it a useful one for studying the organizing influence of drugs on behavior.

We decided to test the value of the runway technique for measuring the organizing influence of reinforcers by using a slightly different experimental method. Water-deprived rats were trained in a runway with water in the goal box. When they had learned to run, they were given four daily home cage pairings of a flavored solution followed by a reinforcer. They were then given five runway trials per day for 2 days. On each of these two test days, there was water in the goal box on the first two trials so thatst two trials so that the animals’ running speeds on Trials 2 and 3 followed experience with this reinforcer. The speeds on these trials were used as a baseline measure. On Trial 3 and on subsequent trials, the paired solution that provided the conditioned taste stimulus was placed in the goal box. The effect of the conditioned taste stimulus on the animals’ tendency to approach the goal box was measured by observing the change from baseline in running speed that its introduction caused.

Natural Reinforcers

In our first experiment we paired drinking the flavored solution with drinking a sucrose solution on the four pairing days. The effects of this pairing on running speed are shown in Figure 8. In Group A introduction Group A introduction of the conditioned taste stimulus on Day 1 had no effect on running speed, but its introduction on Day 2 resulted in a significant increase in running speed. The hypothesis that this increase was caused by learned properties of the conditioned taste stimulus is supported by the results for two control groups. Group B experienced pairings of the flavored solution with water on the four pairing days. Introduction of the taste stimulus into the runway had no effect on running speed. Group C experienced pairings with the sucrose solution, but the conditioned taste stimulus was never introduced into the runway. These rats showed a decrease in running speed on the trials where the rats in Group A increased. Therefore it seems likely that theems likely that the increase in running speed observed in Group A was due to the conditioned properties of the taste stimulus acquired during the pairings. These findings suggest that the method is able to detect a rewarding influence on behavior.

The fact that the increase in running speed occurred only on the second day of testing in the runway might be explained by postulating a requirement for a secondary conditioning process in which the conditioned properties of the taste stimulus become associated with the environmental stimuli that constitute the goal box. If this process occurs on the first test day, then the appearance of the increase would be delayed until the second test day. To test this hypothesis, we paired the flavored solution withvored solution with sucrose but did not introduce the conditioned taste stimulus into the runway on the first test day, thus preventing the occurrence of the suggested conditioning process (Group D). When the taste stimulus was introduced on the second day of testing, no change in running speed was observed, supporting the hypothesis that some process involving the conditioned taste stimulus takes place in the goal box on Day 1. As a second test the animals in Group E experienced the pairings of flavored solution and sucrose in the goal box of the runway, allowing both the primary and postulated secondary conditioning processes to occur together. The rats in this group showed a large increase in running speed when the taste was introduced into theintroduced into the goal box on the first test day. This suggests that the increase in running speed on Day 2 occurs when the organizing influence of the reinforcer becomes associated with the environmental stimuli of the goal box. When this process is prevented from occurring during the initial pairing (e.g., when the pairings are done in the home cage), then it occurs on the first test day and the organizing influence of the reinforcer is detected in the runway on the second test day.

These findings suggest that the rewarding influence of a sucrose reinforcer can become associated with a taste stimulus which can, in turn, become associated with place or environmental stimuli in the runway. Both of these processes are consistent with what we have observed for natural reinforcers using the taste and place conditioning methods separately, since both methods are able to detect the rewarding effect of a natural reinforcer. Our next step was to test the runway method with amphetamine, and, as we had found when using the taste and place methods separately, the drugs has its own properties in this situation.
 

 
Effect of introduction of conditioned taste stimulus on running speed
Figure 8: Effect of introduction of conditioned taste stimulusb> Effect of introduction of conditioned taste stimulus on running speed. The letters at the top of the figure are group identification labels and show the numbers of subjects in each group. In each pair of bars the first one is the mean change in running speed observed on the first test day; the second is the same data for the second test day. On pairing days the animals drank a solution of 2% instant decaffeinated coffee in distilled water for 5 minutes followed by drinking the reinforcer for 25 minutes. The experimental conditions for each group are shown on the abscissa. The line labeled "Test Flavor" shows whether coffee ("C") or water ("W") was available in the goal box on Trials 3 to 5 (Water was always used on Trials 1 and 2.). The line labeled "Pairing Condition" shows whether coffee was paired with sucrose (4% in distilled water) or water on the four pairing days. Significant changes in running speed were: Group A, Day 2: t (18) = 2.32, p < 0.05; Group E, Day 1: t (6) = 2.15, p < 0.05.
 

 Amphetamine

In this experiment the animals were pretrained in the runway and experienced four pairings of novel taste with an injection of saline or with one of two doses of amphetamine. They were then given two days of runway testing. As shown in Figure 9, a substantial aversion to the paired flavor was observed during the pairings, and large dlavor was observed during the pairings, and large decreases in speed were observed when the conditioned taste stimulus was introduced into the runway on both test days. The interpretation of these decreases, that the reinforcer has aversive organizing properties, is consistent with previous taste conditioning data but not with previous findings using other place conditioning methods. The fact that the method detected a sizable aversive effect of 0.5 mg/kg of amphetamine suggests that it may be a very sensitive measure of aversion, and it may even be the case that the decrease in running speed observed in the saline group reflects the aversive properties of the injection procedure. Since these data are the first collected using this method, further investigation of its properties will be necessary before any of these data can be considered firm.

Summary

The present version of the place conditioning method deserves further investigation because it may provide an additional sensitive method for detecting the organizing influence on behavior of reinforcers in general and of drugs in particular. It appears to be able to detect both rewarding and aversive influences, and it has the advantage that the reinforcer need never become directly associated with the test apparatus, thus decreasing the possibility of interference with ongoing behavior by direct or conditioned peripheral actions of drug reinforcers. An apparent diions of drug reinforcers. An apparent disadvantage of this method is that it can detect only those organizing influences which can become associated with taste stimuli; this is illustrated by the purely aversive response to amphetamine. The runway method, in which both conditioned and unconditioned stimuli are present in the goal box, has the advantage of being able to measure two organizing influences simultaneously. However, in cases where the dual method poses difficulties of interpretation, the method of pairing outside the apparatus may offer certain advantages.

Conclusion

Our approach to the study of the reinforcing properties of drugs is through an examination of the reinforcement process itself. Accordingly, we conduct parallel studies of the effects on behavior of both naturally occurring and drug reinforcers, using several different experimental methods. Our goal is to determine the neural basis of the change in behavior produced by reinforcers. One property of natural reinforcers is their rewarding or aversive stimulus properties, which are objectively observable as tendencies to produce approach and maintenance of contact with the reinforcer or to produce withdrawal from it. Therefore, reinforcers are viewed as organizing influences on behavior, and the tendency of animals to approach them or to withdraw from them can be observed in order to determine their stimulus pred in order to determine their stimulus properties.

Although reinforcing drugs have stimulus properties, they lack external reference points for approach or withdrawal. Therefore, the organizing influences of drugs on behavior can be detected only when they are associated with neutral stimuli in a conditioning paradigm and then inferred from responses to the conditioned stimuli. We have examined three methods for accomplishing this.  

 
Effects of amphetamine on running speed
Figure 9: Effects of amphetamine on running speed. The inset shows the mean amount of coffee-flavored solution consumed by the ratsfee-flavored solution consumed by the rats in each group on the four pairing days. There is a significant difference among the means on the fourth day [F (2,17) = 3.63, p < 0.05]. The main part of the figure shows the change in running speed produced by introduction of the coffee solution (for all groups) on test Days 1 and 2, according to the format described for Figure 8. Each bar shows the standard error of the mean and the number of subjects. In the saline group there was a significant decrease on Day 1 [t (6) = 2.69, p < 0.05]. In the 0.5 mg/kg group there was a significant decrease on Day 1 [t (6) = 2.65, p < 0.05]. In the 2.0 mg/kg group there was a significant decrease on Day 1 [t (5) = 3.14, p < 0.03] and on Day 2 [t (5) = 3.79, p < 0.01].
 

It is well known that the taste conditioning method detects the aversive properties of a variety of reinforcers, including self-administered drugs such as morphine and amphetamine. We have shown that it can also detect the rewarding properties of self-stimulation and of sucrose and saccharin solutions. However, it does not appear to detect any rewarding properties of amphetamine.

The place preference conditioning method can detect the rewarding and aversive properties of natural reinforcers, and we present data showing a linear relationship between an ascending series of sucrose concentrations and preference. Furthermore, the place preference method may be a somewhateference method may be a somewhat more sensitive detector of reward than the taste conditioning method. Place conditioning is a highly sensitive detector of the rewarding effects of amphetamine; this was demonstrated by a significant dose-preference relationship for this drug.

The place conditioning runway method described here can detect the rewarding properties of a natural reinforcer, and there is some evidence that it is also a highly sensitive detector of aversion. However, the problems of interpretation posed by our data require further analysis. The runway method in which animals experience food and drug in the goal box has certain advantages over the one described here.

Some data are presented in support of the hypothesis that amphetamine’sis that amphetamine’s influence on behavior is mediated by actions of the drug on more than one neural substrate. Microinjections of the drug into nucleus accumbens give evidence of reward using the place preference method, and similar injections into the region of area postrema give evidence of aversion using the taste conditioning method. These data suggest that amphetamine acts at these two sites with opposite influences. More experiments will be necessary to verify this conclusion and to determine if amphetamine has additional actions at other brain sites.

We attribute the fact that the rewarding and the aversive influences of amphetamine were detected with different methods to associative bias—the notion that the brain is organized to favor the association of certain stimuli. Support for this notion comes from suggestions that reward may be better detected with the place method and aversion better detected with the taste method. However, the concept of associative bias remains an "intervening variable." It will be necessary to find independent corroborating evidence and to determine the neural basis for the proposed biases before it can be accepted as an accurate explanation of the observed phenomena.

Acknowledgments

The research reported and the preparation of this manuscript were supported by grants from the Natural Sciences and Engineering Research Coutural Sciences and Engineering Research Council of Canada and from Fonds FCAC, Province of Quebec. We thank Smith-Kline and French, Canada Ltd. for the gift of amphetamine.

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