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Reprinted from W.M. Davis and S.G. Smith (1987), Conditioned reinforcement as a measure of the rewarding properties of drugs. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (199-210). New York: Springer-Verlag.

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Chapter 11

Conditioned Reinforcement as a Measure of
the Rewarding Properties of Drugs

W. Marvin Davis and Stanley G. Smith*

Department of Pharmacology
School of Pharmacy
The University of Mississippi
University, Mississippi 38677


Abstract
A review is presented of the development and application of a conditioned reinforcement measure for evaluating drug-based primary reinforcement. This procedure has employed both contingent and noncontingent association of the initially neutral stimulus with repeated doses of the drug reinforcer. Evidence for primary reinforcement by doses of drug is later demonstrated by the behavior of a subject when the stimulus is presented contingent to lever-pressing responses. This method allowed testing of potential antagonist drugs for an ability to oppose or cancel the reinforcing action of agents such as dexamphetamine, morphine, and ethanol. Inhibitors of critical enzymes in catecholamine biosynthetic pathways (e.g., tyrosine hydroxylase or dopamine ß-hydroxylase) were found to oppose the reinforcing action of such classical drugs of abuse. The ability of conditioned reinforcement tests to avoid the factor of performance deficits induced by many potential antagonist drugs constitutes a major advantage over a more direct evaluation of drugs for possible interactions with primary reinforcing actions of abuse agents.

 

Introduction

At the beginning of the 1970s, we began investigations of the role that central nervous system (CNS) biogenic amines play in the production of drug-based reinforcement. Our initial efforts centered on the development of experimental protocols to ensure the validity and reliability of planned research on opiate- and amphetamine-based reinforcement. We perceived that previous self-administration research had not ruled out completely the possibility that such drugs were only pseudo-reinforcers, functioning as performance facilitators. That is, previous studies had not controlled for the possibility that drug delivery might merely have increased the general baseline of motor behavior, thus mimicking reinforcement. Also, we soon became aware that pharmacological tools that we wished to employ for the study of CNS adrenergic functions could alter a data baseline via inhibition of motor function, independently of their effects in the central processes related to

*Present address: Choctaw Community Mental Health Center, Philadelphia, Mississippi drug-based reinforcement. Again, this raised the possibility that data generated using such agents might reflect pharmacological side-effects. Therefore, it seemed imperative to find methods that could validly demonstrate drug-based reinforcement without performance artifacts and that would allow the manipulation of the CNS neurotransmitter systems by means of pharmacological tools without unwanted actions such as motor inhibition, motor disinhibition, or the introduction of nonreinforcement factors into the reinforcement measure.

The area of intracranial self-stimulation research seemed both to suffer parallel problems and to provide a means for circumventing such problems in valid measurement of reinforcement associated with nonclassical sources of reward (Liebman, 1983; Valenstein, 1964). Stein (1958) reported that electrical stimulation of the brain in rats had the capacity to impart secondary reinforcing properties to an originally neutral stimulus. This was accomplished by means of four daily pairing sessions with 100 presentations of a 1.0-second tone given concurrently with a 0.5-second train of electrical stimuli delivered to the brain. Three days following the pairings, a 1-hour test session was conducted in which the rats had access to two levers, and only one lever activated the same 1.0-second tone as in the pairings. This lever had been nonpreferred in a baseline session before the pairings. The no-tone lever only measured general motor activity. Test results showed that the lever-pressing on the tone-producing lever had increased significantly in subjects for whom the brain stimulations were subsequently proven (by giving an opportunity to lever-press for the brain stimulation) to have been positively reinforcing. Subjects whose electrodes were found to give a neutral response (i.e., lacking positive reinforcement) showed neither a change in lever preferences nor an increase in rate of lever-pressing subsequent to tone-stimulation pairings.

We saw Stein's experimental design to be applicable to our aims, substituting small intravenous (i.v.) drug doses for electrical brain stimulation. It provided a means of testing for reinforcement, allowing simultaneous recording of data to control for drug-produced changes in motor activity and thus avoiding performance interpretations. It permitted testing for the reinforcer's stimulus control in the acquisition of a newly learned response, further weakening the performance interpretation. It allowed testing for an interaction between the primary reinforcer and a pharmacological tool several days after the pairings. This would permit actions of the drug or tool to be dissipated and CNS functions to be restored to normal. Therefore, we employed these procedures in a conditioned reinforcement approach to studying intravenous doses of morphine and amphetamine for their reinforcing capacities.

Conditioned Reinforcement after Noncontingent
Intravenous Doses of Morphine and Amphetamine

At the outset we established conditions under which drug-naive rats would show apparent evidence of primary reinforcement (i.e., would develop self-administration behavior for intravenous doses of either morphine sulfate or dexamphetamine sulfate solutions; Davis & Smith, 1972). Then, using the drug doses found effective in that situation, we demonstrated conditioned reinforcement produced concurrently with acquisition of self-administration behavior for each of these agents by drug-naive rats (Smith & Davis, 1973a; Davis & Smith, 1974a). Subsequently, we tested for the establishment of conditioned reinforcement with a buzzer stimulus when pairing of the buzzer sound was contingent with programmed drug infusion (i.e., drug effects were noncontingent with behavior; Davis et al., 1972; Davis & Smith, 1974a). We will focus our attention herein on this latter paradigm. An initial experiment aimed at validating the conditioned reinforcement approach was to demonstrate a magnitude of reinforcement or dose response relationship for intravenous doses of morphine employed to establish a conditioned reinforcer (Crowder, Smith, Davis, Noel, & Coussens, 1972). The subjects were allowed a baseline period for determining the operant level of bar-pressing. Here there were no drug contingencies associated with such behavior. However, a 0.2-second neutral buzzer stimulus occurred with each response on the lever, concurrently with an injection of saline solution. At the end of the operant-level period, the lever was removed from the chamber. After one hour a second session began with 100 noncontingent morphine injections given concurrently with buzzer presentations. Morphine doses (as the sulfate) were given to three groups at either 0.0032, 0.032, or 0.32 mg/kg in the same volume and duration as for the prior saline doses. These small morphine doses, shown to generate high responding for self-administration (Weeks & Collins, 1971), were delivered randomly without regard to behavior. The sessions lasted about 200 minutes.

After the pairing sessions the lever had remained out of the chambers until the following day, when it was restored at the same time of day as the initial operant level session. Conditions of that first session were repeated: A lever-response produced the buzzer stimulus plus a saline infusion. This comprised a test for establishment of secondary reinforcing potency for the buzzer stimulus. Immediately after this test a further session began in which lever-pressing led to delivery of the buzzer stimulus plus the same dose of morphine as had been given on the previous day. This period was used to detect any subjects that did not respond for morphine solution as a primary reinforcer. Rats not sensitive to morphine as a primary reinforcer could not be expected to develop conditioned reinforcement. The data for six subjects were eliminated on this basis.

Results of the test for conditioned reinforcement are shown in Figure 1. The baseline operant responses of the groups did not differ, but after the buzzer-morphine pairings their responses were elevated in a dose-related manner (ANOVA, p < 0.01); there was a significant linear trend with log dose (p < 0.01). These results confirmed that repeated small intravenous doses of morphine sulfate paired with a buzzer stimulus had imparted reinforcing properties to the buzzer stimulus and that the magnitude of this reinforcement increased linearly with the unit dose of morphine injected. Absence of withdrawal signs indicated that the amount of morphine administered was insufficient to induce acute physical dependence (Coussens, Crowder, & Smith, 1973).

Another validating study (Davis & Smith, 1974a) used a two-lever condition like the procedure employed by Stein (1958). This was conducted with dexamphetamine sulfate as the reinforcer at a dose of 0.015 mg/kg; 100 pairing trials were given on Day 2, and the test for conditioned reinforcement was on Day 6 rather than Day 3. Half of the subjects received the buzzer stimulus plus saline infusions for responses on the left lever, and the other half received the same combination for responses on the right lever. Responding on the inactive lever had no scheduled consequence, but it was recorded as a measure of nonspecific activity. A much higher number of responses occurred on the reinforced lever than on the other (mean 147.2 vs. 17.2), attesting to the specificity of this behavior as measuring conditioned reinforcement. This demonstration eliminated conditioned activation or disinhibition of motor performance as explanations of the conditioned effect. More extensive data for dexamphetamine were reported later (Davis, Smith, & Khalsa, 1975) along with similar results for morphine in the two-lever design (see Figure 2).
 

 
Dose-response analysis of conditioned reinforcement
Figure 1: Mean number of lever presses during a 6-hour test for conditioned reinforcement with a buzzer-saline infusion contingency 24 hours after 100 buzzer-morphine infusion pairings. Morphine sulfate in the indicated doses was rapidly injected intravenously in a small volume coincident with a 0.5-second buzzer presentation. The lever was out of the chamber during pairings. (n = 7 or 8/group.) Reprinted with permission from Crowder, Smith, Davis, Noel, and Coussens, 1972. Copyright 1972 by Denison University. 
 

Another study confirmed that the level of responding in a test for conditioned reinforcement did not diminish if the test was delayed further—even to 8 or 16 days after the pairing trials—provided that no extinction procedure intervened (Davis & Smith, 1974a). This finding is in accord with what is known for traditional, nondrug reinforcers used as the basis for secondary reinforcement.

CONDITIONED REINFORCEMENT METHOD IN STUDIES
FOR ANTAGONISM OF MORPHINE OR AMPHETAMINE ACTIONS

The successful application of a conditioned reinforcement method to measure a dose-related variation in magnitude of reinforcement from intravenous morphine, and the several other initial validation studies, encouraged our further use of this approach to test whether depletion of CNS catecholamines (CA) might prevent the primary reinforcing action of morphine and dexamphetamine. Despite indications that this might be the case based on our self-administration studies (Davis & Smith, 1972), we felt the need to verify such data by means of the conditioned reinforcement paradigm to preclude motor inhibition or performance factors having possibly contaminated the former data. The general procedure of the initial studies described above was adopted following a 4-step, 7-day format; Day 1 consisted of a 6-hour operant baseline session in which lever presses caused saline infusions. On Day 2 the response levers were removed from the chambers, and the rats received three intraperitoneal injections of either alpha-methyl-para-tyrosine (AMT) or saline solution at 8, 4, and 0 hours before starting an experimental session consisting of 100 noncontingent pairings of the buzzer stimulus and a rapid intravenous injection of morphine sulfate solution (0.032 mg/kg) on a variable-frequency programmed schedule. On Day 6 the rats were again placed in the chamber for the test of conditioned reinforcement under the buzzer-saline contingency as on Day 1. The interval between second and third stages (Day 2 to Day 6) of the experiment permitted recovery from the depression of brain CA levels produced by AMT (Davis & Smith, 1974b). On Day 7 the rats were given a test for possible failure to show primary reinforcement with the dose of morphine used. Only one of 20 rats failed this test and was consequently excluded. The results of the Day 6 test showed that the group of rats (n = 9) receiving AMT before the morphine-buzzer pairings did not respond above their initial operant level on the saline-buzzer condition. However, subjects receiving only saline pretreatment prior to morphine-buzzer pairings showed lever-pressing nearly three times their baseline level, a highly significant difference (p < 0.001) both from their own baseline and from the AMT group. These data indicate that AMT blocked the primary reinforcing action of morphine and thus prevented the establishment of conditioned reinforcement associated with the buzzer stimulus, which was clearly present for the saline pretreated rats. As the test for reinforcement was 4 days after the dosing with AMT, it is not reasonable to suppose that the failure to show reinforcement was caused by an impairment of performance. Thus, these data added strong confirmation to the self-administration data, supporting the conclusion that AMT did indeed block the rewarding effects associated with small intravenous doses of morphine (Davis & Smith, 1973a).
 

 
Two-lever test during conditioned reinforcement
Figure 2: Two-lever validation data for self-administration (SA) and conditioned reinforcement (CR) paradigms with rats receiving morphine sulfate in intravenous doses of 0.032 mg/kg during SA or in 100 noncontingent pairings with buzzer 1 day before the CR test. R indicates responses on the reinforced lever for the SA test or the lever producing the buzzer in the CR test; A indicates responses on the lever having no contingencies associated, providing only an index of general activity. Adapted with permission from Davis, Smith, and Khalsa, 1975. 
 

Parallel studies performed with dexamphetamine sulfate and AMT (Davis & Smith, 1973b), as with morphine, gave results also parallel to those for morphine. Not only the data for self-administration but also those for the conditioned reinforcement procedure showed a blocking of dexamphetamine-associated primary reinforcement.

Further application of the conditioned reinforcement paradigm was directed to the possible discrimination between noradrenergic and dopaminergic components in the effects of AMT on reward from both morphine and dexamphetamine. Both sodium diethyldithiocarbamate (DDC) and U-14,624 (inhibitors of dopamine b-hydroxylase, which is the enzyme that controls the biosynthetic step between dopamine and norepinephrine) were employed for this purpose (see Figure 3). On the basis of studies with DDC and U-14,624 analogous to those with AMT, it appeared that production of a noradrenergic deficit in this manner could prevent the rewarding action of either morphine or dexamphetamine (Davis et al., 1975).

A particular advantage of the conditioned reinforcement test may be seen in the results of an interaction study of morphine and the dopamine-receptor blocking agent haloperidol (Smith & Davis, 1973b). In this case pretreatment with two large doses (5 and 10 mg/kg) of haloperidol prevented reacquisition of morphine self-administration behavior. However, the same and even higher doses of haloperidol failed to impair the responding in the conditioned reinforcement test of rats that had received haloperidol before the morphine-buzzer pairings. Thus, it was concluded that the former results had reflected a motor inhibitory action of haloperidol rather than a blocking of morphine's rewarding action. This is particularly noteworthy in light of the fact that a lower haloperidol dose (0.5 mg/kg) in both paradigms showed evidence for enhancement of the reward potency of morphine.

In contrast to morphine, dexamphetamine-associated reinforcement was effectively blocked in both experimental designs by haloperidol (Davis & Smith, 1975). Moreover dopamine-receptor antagonism by means of haloperidol also appeared to explain the antagonism of reinforcement associated with two dopaminergic agonists, apomorphine and piribedil (ET-495), both in self-administration and conditioned reinforcement tests (Davis & Smith, 1977). Depletion of brain norepinephrine via U-14,624 treatment, however, was ineffective in altering the rewarding potency of apomorphine (see Figure 4). Similarly, a noradrenergic agent, clonidine, which supported both self-administration and conditioned reinforcement, could be blocked from exerting its primary reinforcing action by the noradrenergic receptor blocker phenoxybenzamine. A lack of cross-effectiveness both of phenoxybenzamine versus apomorphine and piribedil, and of haloperidol versus clonidine, was demonstrated solely on the basis of the conditioned reinforcement procedure. These results constituted a pharmacological validation for the earlier studies of this paper (Davis & Smith, 1977).
 

 
Effects of dopamine beta-hydroxylase inhibitors on conditioned reinforcement
Figure 3: Effects of two dopamine b-hydroxylase inhibitors (DDC and U-14,624) on establishment of a conditioned reinforcer in rats based on intravenous doses (0.032 mg/kg) of morphine sulfate paired 100 times with a neutral buzzer stimulus. Groups C received the drug vehicle treatment, while Groups E received one of the inhibitors before the pairings session. The CR test was 4 days after the pairings. Data are means (± SEM) for groups of 8 subjects. Adapted with permission from Davis, Smith, and Khalsa, 1975. 
 

Conditioned Reinforcement Method in
Research on Intragastric Ethanol

Ethanol is a considerably weaker reinforcer than is morphine or dexamphetamine even if they are compared by intravenous injection (Smith & Davis, 1974; Smith, Werner, & Davis, 1975a). Moreover, to model its human use/misuse, the oral rather than intravenous route of administration is much to be preferred (see also Amit, Smith, & Sutherland, this volume). In order to avoid problems associated with voluntary oral intake of ethanol solutions by rats while maintaining the intragastric mode of absorption, we developed an intragastric (i.g.) cannulation technique that proved applicable to self-administration experiments (Smith, Werner, & Davis, 1975b). The delay imposed by the intragastric route caused a different dose-response relationship for self-administration than resulted if the same doses were made available intravenously (Smith, Werner, & Davis, 1976). Despite these facts the buzzer stimulus that overlaid self-administered 100 mg/kg intragastric doses of ethanol was found to act as a conditioned reinforcer, increasing responding during extinction on saline contingency trials (Smith, Werner, & Davis, 1977; see Figure 5). Furthermore, the response-noncontingent pairing of a buzzer stimulus with experimenter-delivered doses of ethanol (25, 50, or 100 mg/kg, i.g.) 50 times per day for 4 days resulted in a dose-related gradation of responding in a subsequent 10-hour test of conditioned reinforcement on buzzer-saline contingency (see Figure 6).
 

 
Conditioned reinforcement from intravenous apomorphine
Figure 4: Conditioned reinforcement in rats based on intravenous doses of apomorphine (0.06 mg/kg) paired with a neutral buzzer stimulus in a 100-trial session. Group indicated HAL received 5 mg/kg of haloperidol before beginning the pairings session, while group marked U-14 received U-14,624 before pairings. Reprinted with permission from Davis and Smith, 1977. Copyright 1977 by Pergamon Press Inc. 
 

Experiments regarding the role of brain catecholaminergic systems in the rewarding action of ethanol were conducted in analogous fashion to those described above for morphine and dexamphetamine. The differences were the use of the intragastric route and a longer (10-hour) session for acquisition of self-administration behavior and in testing for conditioned reinforcement. First studied were AMT and U-14,624, which blocked ethanol self-administration (Davis, Smith, & Werner, 1978). This was followed by a similar study of FLA-57, another inhibitor of dopamine b-hydroxylase, which was fully effective against both reacquisition of self-administration behavior and responding in the test for conditioned reinforcement (Davis, Werner, & Smith, 1979).
 

 
Extinction responding following conditioned reinforcement training
Figure 5: Demonstration of effects on extinction-responding of a conditioned reinforcer established by intragastric doses of 25 or 100 mg/kg of ethanol given contiguously with a buzzer stimulus during five daily 10-hour self-administration sessions. Data are means (± SEM) of lever responses under extinction on Day 6. Buzzer and saline injection were contingent upon lever pressing in one-half of each dose group, while the other half received saline injection but no buzzer. Reprinted with permission from Smith, Werner, and Davis, 1977. Copyright 1977 by Springer-Verlag.
 

Discussion

Research on conditioned reinforcement and opiates prior to or at the time of our initial studies (Schuster, & Woods, 1968; Stolerman & Kumar, 1972; Wikler, Pescor, Miller, & Norrell, 1972) employed physically dependent organisms that required a lengthy dependence induction phase. Thus, our data first demonstrated conditioned reinforcement in nondependent subjects. Prior researchers also had required an operant-response-contingent relationship between the neutral stimulus (to become the conditioned reinforcer) and the primary reinforcer, morphine. We introduced the classically conditioned relationship. A reinforcement interpretation requires evidence of learning. The conditioned reinforcer must be validly demonstrated to control the dependent variable--in this case the lever-response or drinking rate—as a learned phenomenon. Since the putative conditioned reinforcers in the early studies cited were tested during opiate abstinence, increased responding could have been caused by disinhibitory factors (such as increased motor or drinking activity) related to withdrawal stress or facilitation of locomotor activity or drinking patterns introducing performance artifacts. Therefore, at the time of our studies, no unconfounded data were available which clearly showed that truly learned, secondary reinforcement phenomena were demonstrable in drug-reward research.

Thus, our first efforts were to demonstrate opiate-based primary reinforcement and conditioned reinforcement in nondependent organisms in such ways as to avoid both dependency and performance factors probably contaminating previous data. Next, we undertook to develop valid measures for the study of drug-based conditioned reinforcement, valid being defined as methods uncontaminated by performance variables. This was accomplished by our Pavlovian pairing method which incorporated a new learned instrumental response as its basic measure. Furthermore, we examined the reliability of our results in terms of ability to replicate our data. This was accomplished not only by direct replications of our original results but also by means of cross-reliability studies—by showing magnitude of reinforcement effects, by delayed testing for acquisition of conditioned reinforcer, and by systematic replication showing conditioned reinforcers associated with orthogonal primary reinforcers (i.e., other drugs such as amphetamine and apomorphine and later ethanol).
 

 
Dose-response analysis for conditioned reinforcement from ethanol
Figure 6: Dose-relationship in a test for conditioned reinforcement with groups that received 0, 25, 50, or 100 mg/kg intragastric doses of ethanol paired with a buzzer stimulus. Pairings were 50 per day for 4 days with the lever removed from the apparatus. The conditioned reinforcement test was a 10-hour session with levers restored and a buzzer-saline contingency like the operant baseline period. Reprinted with permission from Smith, Werner, and Davis, 1977. Copyright 1977 by Springer-Verlag.
 

Beyond these methodological considerations there is a considerable significance of drug-based conditioned reinforcement to the clinical bases of drug abuse syndromes. We have described animal experiments directed to the analysis of roles played by conditioned reinforcers in maintenance and/or relapse to drug-seeking behavior (Davis & Smith, 1976). Not only the latter research area but also the utilitarian applications of conditioned reinforcement as a measure of reward from abused drugs merit further attention and exploitation by researchers on drug abuse.

Acknowledgements

This research was supported by research grants MH 13570, MH 11295, and DA 00018 from the National Institute of Mental Health/National Institute on Drug Abuse and by the Research Institute of Pharmaceutical Sciences of the University of Mississippi.

References

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