Psychopharmacology (1985) 86:212-216 Psychopharmacology �9 Springer-Verlag 1985

The effects of methadone on operant behavior maintained with and without conditioned reinforcement in the pigeon

Thomas H. Kelly 1' 2 and Travis Thompson 1

1 Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA 2 Veterans Administration Medical Center, Shreveport, LA 71130, USA

Abstract. Effects of methadone on key pecking supple- mented with brief stimuli either correlated with or indepen- dent of unconditioned reinforcement was investigated. On average, key pecks by pigeons produced brief stimuli (BS) once per minute and food once per 4 rain during both com- ponents of a multiple schedule (i.e., VI1 :BS, VI4:Food). Brief stimuli were paired with food presentation during one component and not related to food during the second com- ponent. Acute methadone administration (0.56, 1.0, 1.7, and 3.0 mg/kg) decreased response rates during both com- ponents; however, the decrease was smaller by a constant amount during the paired brief stimulus component, re- gardless of drug dose. These results suggest conditioned reinforcement is not a primary mechanism through which methadone exerts behavioral effects and that reinforcer-cor- related stimuli have potential for diminishing the reduced behavioral output observed following methadone adminis- tration.

Key words: Methadone - Operant performance - Condi- tioned reinforcement - Pigeons

The qualitative nature of a reinforcing stimulus has tradi- tionally been considered a less powerful predictor of drug- behavior interactions than the temporal patterning of re- sponding engendered by reinforcer presentations (Kelleher and Morse 1968; Iverson and Iverson 1975). Recent evi- dence suggests that the nature of the maintaining event is also of critical importance. Drugs differentially affect identical patterns of responding maintained by different events (Barrett and Katz 198/).

Certain drugs also alter the reinforcing efficacy of main- taining events. For instance, narcotic antagonists diminish the efficacy of narcotic agonists at doses that have little effect on other maintaining events (e.g., Meyer et al. 1976; Goldberg et al. 1971). Amphetamine selectively alters the reinforcing efficacy of sweetened milk in rats at low dos- ages; higher dosages (2-3 mg/kg) also affect motor perfor- mance (Heyman 1983). The effectiveness of conditioned reinforcers may also vary with administration of the stimu- lant, pipradrol. Hill (1970) found pipradrol enhances the rate-sustaining properties of a conditioned reinforcer during extinction. Robbins and Koob replicated these findings us-

Offprint requests to: T. Thompson

ing additional controls and unconditioned reinforcers (Rob- bins 1975, 1978; Robbins and Koob 1978). They also found pipradrol improves the efficacy of these stimuli for condi- tioning new operants. Other stimulants have equivocal ef- fects on conditioned reinforcer efficacy (Robbins 1978).

The reinforcing properties of maintaining events, there- fore, serve as viable mechanisms through which drugs may affect behavior. It remains unclear whether these interac- tions reflect a change in the quality of reinforcing stimuli (e.g., Heyman 1983) or an alteration of the conditioning properties of reinforcers (e.g., Galbicka and Platt 1984).

Thompson and Weiss (1984) investigated the possibility that methadone might diminish the reinforcing efficacy of conditioned reinforcers using an extinction procedure simi- lar to Hill's 0970). They found methadone does not selec- tively alter the behavioral effects of reinforcer-correlated stimuli. Rather, the presence of these stimuli effectively ameliorates behavioral decreases resulting from methadone administration. It appeared methadone has no selective ef- fect on the efficacy of conditioned reinforcers.

Unconditioned reinforcers are not present while testing for conditioned reinforcer viability during extinction; there- fore, the occasional temporal pairing necessary to maintain reinforcer potency is absent. Since the efficacy of condi- tioned reinforcers decreases during such testing, any inter- action between methadone and conditioned reinforcement may have been obscured. The present experiment extended the Thompson and Weiss (1984) findings using, a schedule that maintained occasional stimulus-reinforcer pairings. Pi- geons received food following key pecks under a variable interval of 4 min (VI4) schedule during both components of a multiple schedule. During one component, brief stimuli paired with food delivery (PS) were presented following key pecks after variable intervals of 1 rain (VI1) indepen- dent of scheduled food reinforcement. Conditions during the second component were identical except brief stimuli were not paired (NS) with food presentation. By assessing the relative extent to which performance was affected dur- ing these components, it was possible to further evaluate whether methadone interacts with conditioned reinforcing properties of a reinforcer-correlated stimulus.

Materials and methods

The subjects were four drug-naive male adult White Car- neaux pigeons, maintained at 80% free-feeding weights by postsession feedings of Purina Pigeon Chow. All were indi-

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vidually housed in colony rooms maintained at 24 ~ C with 24 h light illumination. Water and grit were continuously available.

Apparatus, Experimental sessions were conducted in com- mercially available, ventilated, sound-attenuating cubicles (two small universal cubicals 132-02, two small universal cubicals 132-03, BRS/LVE, Laurel, MD) each with two key intelligence panels (two BRS/LVE model 141-10, two BRS/LVE model 141-15) and solenoid-operated feeders (BRS/LVE model 114-10). Two chamber keys were transil- luminated with equipped six color lamps (Dialco 3917 bulb) and the other two chambers were transilluminated with IEE 12 stimulus projectors (BRS/LVE model IC-901, 1820 bulb). The feeder was illuminated when operated and mixed grain was presented. All chambers were illuminated with house lights (] 820 bulbs) and white noise was continuously present. A second chamber light, located on the ceiling, was used as a control stimulus (1820 bulb). Programming and data recording were accomplished by commercially available electromechanical devices, timers, counters, and cumulative recorders located in an adjacent room.

Procedure. Pigeons were given two sessions of adaptation (20 rain per session) followed by a minimum of two sessions of magazine training until grain was reliably eaten. Pigeons were hand shaped to peck either key when transilluminated white. All subsequent pecks resulted in 5 s food access (CRF). Keys were transilluminated blue and chamber lights extinguished when reinforcement was presented. Once re- sponding reliably occurred, contingencies were changed so that the first peck following variable time intervals, averag- ing 30 s (VI30"), produced food. Average interreinforce- ment intervals were slowly increased until a VI4 schedule was reached. Final contingencies consisted of a two-compo- nent multiple schedule signaled by red and green key illumi- nation. During one component, key pecks produced food according to a VI4 schedule and simultaneously produced brief stimuli paired with food presentation (blue key light, house light removed and feeder illuminated) for 0.5 s ac- cording to a second VI1 schedule. Conditions were identical during the second component except the brief stimuli (over- head light) were never presented following a response that produced food. Therefore, during each component, key pecks produced brief stimuli once per minute and food once per 4 min, on average. Component key color-brief stimulus conditions and key locations were counterbalanced across birds. Each component was presented five times per session, alternating every 4.5 min with 4 s of darkness (time-out) separating components, and the initial component alter- nated every session. Session length was 45.6 min.

Prior to establishing this final contingency, birds were exposed to second-order schedules (VI4:VI30":BS) with the brief stimulus components presented concurrently on separate keys and, later, alternating during a multiple schedule. The second-order contingency resulted in a few short paired stimulus-food or food-food intervals. Pausing and wing flapping following stimulus presentations limited the usefulness of these baselines.

Drug administration. Methadone hydrochloride was dis- solved in isotonic saline to allow constant volume (1 ml/kg) injections. Vehicle (saline) injections were given twice per week (Monday and Thursday). Three stability criteria were

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Fig. 1. Mean response rate as a function of log dose (mg/kg) of methadone for all subjects. Responses produced food on a VI4' schedule and stimuli paired or not paired with food on an interpo- lated VIi ' schedule during the components of a multiple schedule. Solid line represents control rate, dashed line represents _+ 10% of control rate (stability criteria prior to drug administration)

met prior to any drug administration: (1) three of four consecutive daily response rates and paired stimulus re- sponse ratios (total responses in PS components/total ses- sion responses) were within _+10% of the overall 4-day mean; (2) the Thursday vehicle session values were also within this variability range; and (3) no noticeable change in baseline performance was observed. All drugs were ad- ministered before Friday sessions. Methadone, expressed as the salt, was administered at doses of 0.56, 1.0, 1.7, and 3.0 mg/kg. Doses were given twice in an ascending-descend- ing sequence followed by replications. All injections were given IM (breast muscle) 15 min prior to sessions. Birds were returned to home cages following injections. After dose-response determinations, all birds were exposed to ex- tinction, but brief stimulus conditions remained.

Data analysis. The following dependent variables were ana- lyzed: (1) overall response rate (total responses/total session time); (2) overall response rate per component (total re- sponses per component/total time per component); and (3) PS response ratio (total responses during PS component/ total session responses). Dependent measures are occasion- ally presented as a percentage of the preceding saline session value (Thursday) for individual subjects.

Results

Except for a slight decrease in overall key pecking rate at the lowest methadone dose (0.56 mg/kg) by T26, the two lowest doses had little effect on overall key pecking rate (Fig. 1). A log-dose-dependent decrease in overall rate was observed between 1.0 and 3.0 mg/kg. The 50% rate reduc- tion occurred between 1.7 and 3.0 mg/kg for these bids. Effects of methadone on key pecking rates during each component of the multiple schedule are shown in Fig. 2.

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Fig. 2,. Mean rate o f response dur ing each o f two components of a multiple schedule as a function of log dose (mg/kg). Closed circles rate of response during stimulus-paired components; open circles rate of response during non paired components

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Fig. 3. Least square regression lines for percent of saline control rate of response in paired-stimulus (PS, closed circles) and non paired-stimulus (NS, open circles) components as a function of percent of saline control overall rate of response for PS- and NS- terminated components. Data points represent mean values for individual birds at each drug dose. Only sessions during which at least one response was emitted during each component are in- cluded. Subject T30 made no responses during sessions preceded by a 3.0 mg/kg methadone injection; therefore, only 15 data points are included

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Fig. 4. Paired stimulus (PS) response ratio (responses during PS components/total responses) over successive sessions of extinction during which responding occurred for all birds. Horizontal line represents equal rates of responding during PS and NS components

Rates were consistently higher during NS components. As methadone dose increased, responding during each compo- nent decreased, though to a greater extent during NS com- ponents.

The highest doses of methadone (1.7 and 3.0 mg/kg) initially eliminated responding by T26, T29, and T30. Re- sponding gradually increased throughout the session, how- ever, indicating a time course effect. Since components al- ternated during sessions, the component occurring last dur- ing a given drug session occurred at times when drug effects were diminishing and response rates were increasing. There- fore, the interactions between methadone and brief stimuli were analyzed separately for sessions terminating with PS or NS components.

Differential changes in response rates during PS and NS components following methadone administration were examined for evidence of drug-induced changes in the be- havioral effects of the brief stimuli (Fig. 3). The percentage of control response rate during PS and NS components was plotted as a function of overall response rate. In this manner, the behavioral effects of the brief stimuli can be assessed relative to drug-induced changes in overall re- sponding, independent of control response rates. Rates dur- ing the two components decreased equally as overall rate decreased. No interaction between dose of methadone and the behavioral effects of the brief stimulus was evident. Rates were consistently higher in PS components during PS-terminated sessions and equal during NS-terminated sessions.

Higher baseline response rates during NS components raised the question of whether the PS was functioning as a conditioned reinforcer. One way to determine that was to withhold food during each component (extinction). Fig- ure 4 shows that following removal of primary reinforce- ment, PS response ratios gradually increased indicating the

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paired stimulus was functioning as a conditioned reinforcer. A PS response ratio of 0.5 indicates that an equal number of responses were emitted during PS and NS components.

Discussion

Increasing methadone doses resulted in relatively greater response rate reduction during components without the paired stimulus (Fig. 2). Since baseline rates during the components were unequal, relative changes were also ana- lyzed (Fig. 3). Decreases in the percentage of control rates were equal during both components of the multiple sched- ule; methadone did not systematically alter the behavioral effects of the conditioned reinforcer. However, the presence of the paired stimulus diminished methadone-induced rate reduction during PS-terminated sessions and resulted in identical rate reduction in both components during NS- terminated sessions. Thus, it appears methadone produces differential rate reduction during NS components due to the absence of conditioned reinforcing stimuli rather than by enhancing the reinforcing effects of paired stimuli. These results are similar to those of Thompson and Weiss (unpub- lished) using the resistance to extinction method with rats.

It might be argued that the greater rate reduction during NS components is due to the time course effects observed in several birds. A time course effect suggests that the in- verse of the relationship between component rates and over- all rate reductions observed during PS-terminated sessions should occur during NS-terminated sessions. Relatively smaller rate reduction would occur in NS components dur- ing NS-terminated sessions since NS components occurred at the end of sessions. However, rates during each compo- nent were reduced at identical rates during NS-terminated components. One might argue that, given the time course effect, equivalent drug effects during NS-terminated com- ponents offer additional evidence for the ameliorating ef- fects of conditioned reinforcing stimuli.

The EDso for rate reduction between doses of 1.7 and 3.0 mg/kg (Fig. 1) corresponded well with published reports of methadone's rate-reducing effects on performance main- tained under fixed interval (FI) (Young and Thompson, unpublished; Jensen and Thompson 1982; Leander and McCleary 1982) and fixed ratio (FR) (Leander and McCle- ary 1982) schedules in pigeons; FR performance in mice (Middaugh and Santos 1978); and schedule performance in rats (Thompson et al. 1984; McMillan et al. J980; Molin- engo and Ricci-Gamalero 1970). Ratio performance is more sensitive to methadone's rate decreasing effects, even when ratio and interval schedules are equated for frequency of reinforcement (Thompson et al. 1984). However, the EDso in this study was slightly higher than that reported by Bige- low and Thompson (1971) on FR responding by monkeys, and slightly lower than that reported for both FI and FR performance in pigeons (McMillan et al. 1970; McGivney and McMillan 1981) and rats (McMillan and Brocco 1984). In addition to differences in reinforcement contingencies, routes of administration and species selected, variability in individual subject sensitivity to methadone (e.g., Leander and McCleary 1982) may account for potency differences across studies. Methadone disrupts VI performance with a potency equal to that observed during many schedules of reinforcement. No rate-enhancing effect of methadone was found on the VI performance as has been occasionally reported during FI performance (Heifitz and McMillan

1971; McMillan etal. 1970; Woods 1969; McKearney 1975; McMillan and Brocco 1984), and VR performance in rats (Molinengo and Ricci-Gamalero 1970).

The results of this experiment suggest methadone does not alter the efficacy of conditioned reinforcement. Both the nature of the reinforcing stimulus and the conditioning properties of the reinforcer remained constant as the effects of methadone on overall behavior increased (i.e., no interac- tions between the conditioned reinforcer and the methadone dose were observed). Rather, presence of conditioned rein- forcement ameliorated the rate-reducing effects of metha- done. The magnitude of this amelioration (Fig. 3) is likely determined by the reinforcing efficacy of the paired stimu- lus. The viability of a conditioned reinforcer is determined, in part, by the parameters of temporal contiguity between the stimulus and an established reinforcer (i.e,, respondent conditioning, see Dinsmoor 1983). It remains unclear whether changes in the parameters of contiguity between food and the brief stimuli (either paired or nonpaired) will affect this observed relationship between methadone and conditioned reinforcement.

Acknowledgements. The research was supported by the National Institute on Drug Abuse grant 5 R01 DA-02717. We would like to thank Dr. James Cleary for comments on the manuscript and Martin Wurthman for technical assistance. Preparation of the manuscript was supported by the Veterans Administration. These data were included in a thesis submitted to the University of Min- nesota in June 1983 by THK.

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Received September 12, 1983; Final version November 26, 1984