Psychopharmacology (1991) 103:121-128 Psychopharmacology Springer-Verlag 199t

Situational specificity of tolerance to effects of phencyclidine on responding of rats under fixed-ratio and spaced-responding schedules*

James B. Smith

Worcester Foundation for Experimental Biology, 222 Maple Avenue, Shrewsbury, MA 01545, USA

Received December 18, 1989 / Final version May 29, 1990

Abstract. Responding of rats (n = 5) was maintained un- der DRL (lever) and Time-Delay (nose-key) schedules of food presentation in different experimental chambers during two separate daily sessions. Tolerance that de- veloped to rate-decreasing effects of phencyclidine for nose-key pressing under the Time-Delay schedule did not extend to effects of phencyclidine on lever pressing under the DRL schedule. In a second experiment, both lever and nose-key pressing of rats were maintained under individual and multiple fixed-ratio schedules. One group of animals (n = 5) experienced both the individual and the multiple schedules in the same experimental chamber and another group (n = 5) experienced the individual and the multiple schedules in different experimental chambers. Tolerance that developed to behavioral effects of phency- clidine during the individual schedule did not extend to responding on even the same manipulandum under the multiple schedule in a different experimental chamber. In contrast, tolerance that developed to behavioral effects of phencyclidine during the individual schedule did ex- tend to responding on even the different manipulandum under the multiple schedule in the same experimental chamber. Thus, tolerance that developed in the environ- ment that was coincident with the pharmacologic actions of phencyclidine did not extend to similar operants in a different environmental condition, but did extend even to a different operant and schedule context in the same environmental condition.

Key words: Phencyclidine - Behavioral tolerance - DRL - Time-Delay - FR - Rat

*Animals used in this study were maintained in accordance with guidelines of the Animal Care Committee of the Worcester Founda- tion for Experimental Biology and of the "Guide for Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication Number (NIH)85- 23, revised 1985

A number of experiments have demonstrated behavioral influences on drug tolerance by comparing effects of drugs when they are initially administered after, and the before, daily experimental sessions (Siegel 1976; Murray et al. 1977; Smith 1979; Post et al. 1981). Since pharma- cologic effects of post-session drug administration do not typically coincide with behavioral processes associated with experimental procedures, any tolerance that de- velops during such drug administration cannot involve behavioral processes that occur during the experimental sessions. And conversely, when tolerance to behavioral effects of a drug does not develop during post-session drug administration, but then does develop during subse- quent pre-session drug dosing, that tolerance probably does involve behavioral processes associated with the environmental situation and procedures occurring during the session.

Two general kinds of behavioral processes are often considered to influence tolerance to the behavioral effects of drugs. For one, behavioral effects of a chronically administered drug are considered to be influenced by the extent to which initial effects of the drug interfere with normal relations between the behavior and its conse- quences, and there has recently been considerable dis- cussion of ways in which "reinforcer loss" and "compen- satory behavior" may influence tolerance to behavioral effects of many drugs (e.g., Balster 1985; Barrett et al. 1989; Blackman 1989; Wolgin 1989). In the other behav- ioral influence on tolerance, discriminable physiological effects of a drug are considered to become associated with environmental stimuli which are coincidental with drug administration, without regard to specific behavior- al consequences. Several experiments have shown that external situational stimuli develop control over phys- iological responses of certain drugs (Kayan et al. 1973; Siegel 1975, 1978, 1982, 1989; Siegel and Sdao-Jarvie, 1986), and tolerance is considered to result from this associative, or Pavlovian, conditioning.

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Experiments studying influences on tolerance of rein- forcer loss and compensatory operant behavior have not systematically studied the joint influence of associative processes, and experiments studying influences of Pav- lovian associative processes have not systematically stud- ied compensatory operant responding (but see Smith 1979; Sannerud and Young 1986). However, the ex- perience of reinforcer loss invariably occurs in the presence of specific environmental circumstances, and the occurrence of associative conditioning is usually in the midst of instrumental activity, so that the two processes will typically occur simultaneously.

Recent experiments in this laboratory have studied associative influences on drug tolerance using a multi- environment procedure in which the same subjects are studied in different sets of operant circumstances at dif- ferent times each day. With this procedure, a drug that is administered before a second or third daily session also occurs after earlier sessions during the same day. This permits measurement of behavioral effects during con- current before/after drug administration in the same sub- ject and provides a way to systematically study the asso- ciative and discriminative influence of identifiable en- vironmental features on tolerance generalization. In a previous experiment, for example, tolerance that de- veloped to the behavioral effects of cocaine in one en- vironment did not extend to operants maintained under either a different schedule or with a different manipulan- dum when those different operants occurred in a different environmental situation (Smith 1990b). Additionally, tolerance that developed to the behavioral effects of morphine in one environment did not extend to an op- erant maintained under even the same schedule and with the same manipulandum when that operant occurred in a different environmental situation (Smith 1990a). This absence of tolerance generalization for cocaine, mor- phine, and the cannabinoid l-nantradol is similar to that reported previously for tolerance to effects of phency- clidine (Woolverton and Balster 1979) and LSD (Murray et al. 1977) on schedule-controlled behavior of rat, and for tolerance to effects of ethanol on cognitive behavior of humans (Shapiro and Nathan 1986). In contrast, how- ever, there are also reports that tolerance does generalize for effects of physostigmine (Genovese et aI. 1988) and phencyclidine (Murray 1978) on schedule-controlled be- havior of rats, and for tolerance to the effects of ethanol on motor coordination and maze performance of the rat (Leblanc et al. 1975).

Phencyclidine has pronounced behavioral and dis- criminative effects (Balster 1987) which diminish with re- peated administration (Beardsley and Balster 1988). Moreover, phencyclidine is recognized as a widely and illicitly used drug for which tolerance may increase its frequency or dosage in further use. Consequently, it will be helpful to more fully characterize the influence of behavioral processes on tolerance to the behavioral effects of this drug.

The present experiment studied associative influences on tolerance development to behavioral effects of phencyclidine using a multi-environment procedure. In experiment 1, lever and nose-key pressing of rats were

maintained under different spaced-responding schedules of food delivery in different environments. The purpose of this experiment was to study tolerance generalization for responding with different manipulanda, in different environmental circumstances, and under different schedules of food presentation, but involving a putatively similar behavioral process of timing. In experiment 2, lever and nose-key pressing of rats were maintained un- der the same fixed-ratio schedule of food delivery in either an individual or a multiple schedule in either the same or different environments. The purpose of this experiment was to study tolerance generalization for responding in different behavioral contexts, but with the same individual schedule of reinforcement, and in either the same or different environmental situation.

In experiment 1, tolerance that developed to behav- ioral effects of phencyclidine on spaced responding with a nose-key in the environment coincident with the pharmacologic actions of the drug did not extend to spaced responding with a lever in a different environ- mental situation. In experiment 2, tolerance that de- veloped to effects of phencyclidine on FR responding during an individual schedule extended to FR respond- ing during a multiple schedule when the individual and the multiple schedules occurred in the same, but not when they occurred in different, environmental situa- tions.

Materials and methods

Subjects" and apparatus

Fifteen experimentally naive male Charles River CD aIbino rats (F344) were maintained at 300 g body weight and were approxi- mately 6 months old at the start of the experiment. Experiments were conducted with individual rats placed in one of two Model C Rat Cages (23 cm long x 20 cm wide x 20 cm high; Gerbrands Corp., Arlington, Mass.) or in a smaller clear lucite chamber mea- suring 25 cm long x 15 cm wide x 15 cm high. Each Model C Cage contained a response lever (G6312, Gerbrands) centered on a short wall of the chamber and mounted 7.5 cm up from the grid floor; a response key (G6315, Gerbrands) mounted in the lower right corner of the same wall; a recessed food cup (F7020, Gerbrands) mounted in the lower left comer of the same wall, and a water bottle and speaker on the opposite walt. The food cup was connected to a solenoid-operated pellet dispenser (G5100, Gerbrands). One of the Model C cages had standard clear lucite walls and the other Model C cage had walls that were darkened with black construction paper. The smaller clear lucite chamber contained a response lever (G6312, Gerbrands) mounted on one of the 15 cm walls in the lower right corner; a food cup (F7020, Gerbrands) mounted on the same wall in the lower left corner; and a speaker and a water tube on the opposite wall. Sessions in all cages were accompanied by masking noise and a 7-W light mounted either directly over the lever or behind the nose-key. All chambers were enclosed in larger sound attenuating boxes. The control and recording of all scheduled events used an IBM AT-compatible computer with BehaviorPlus TM software developed by Princeton Economics, Inc. (Princeton, Mass.).

Experiment 1

Behavioral procedure. Lever and nose-key pressing were trained by selectively reinforcing desired features of behavior, and responding

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was initially maintained under a one-response fixed-ratio schedule which delivered single food pellets (0.045 g, Noyes) in the presence of a white keylight in the darkened Model C chamber (nose-key pressing) or a white light over the lever in the clear Model C chamber (lever pressing). Lever pressing was subsequently main- tained in daily sessions at 8:00 a.m. in the clear chamber under a schedule in which each response had to be preceded by 30 s of no responding in order for one food pellet to be delivered (Differential- Reinforcement-of-Low Rate; DRL). Food could only follow a response terminating a minimum interval, and intervening re- sponses reset the interval. Nose-key pressing was subsequently maintained in daily sessions at 1:00 p.m. in the darkened chamber under a schedule in which each response had to be followed by 30 s of no responding in order for one food pellet to be delivered (Time- Delay, Dews 1960). Food could only follow a response initiating a minimum interval, and intervening responses reset the interval. Thus, food occurred after a pause and then a response under the DRL schedule, but after a response and then a pause under the Time-Delay schedule. Animals responded under these conditions until variability of response rate for each schedule was within 20% for 2 successive weeks.

Drug procedure. Phencyclidine hydrochloride (phencyclidine HC1; provided by the National Institute on Drug Abuse, Rockville, Maryland) was dissolved in a 0.9% sodium chloride solution and injected IM in a volume of 0.5 ml/kg body weight. Similar volumes of vehicle served as control injections. After initial training, each animal received at least five injections of each of several doses of phencyclidine (0.3-3.0 mg/kg) once weekly in mixed order im- mediately prior to each experimental session. Phencyclidine has a rapid onset of action and the immediate pre-injection permitted observation of initial behavioral effects. When animals received phencyclidine prior to the first session, they were not studied on that day in the second session, Each animal also received at least seven injections of vehicle once weekly immediately prior to each experi- mental session, and the average of these sessions was used for comparing pre-drug control responding with effects of both acutely and chronically administered phencyclidine.

After determination of acute dose effects, animals received 3.0 mg/kg/day phencyclidine for 4 weeks at each of the following times: after Time-Delay responding in the second daily session; before Time-Delay responding in the second session; before DRL responding in the first daily session; and then once again before Time-Delay responding in the second session. During the final 4 weeks, animals also received occasional probe injections of phencyclidine before DRL responding in session 1.

Experiment 2

Behavioral procedure. Lever and nose-key pressing were trained by selectively reinforcing desired features of behavior, and responding was initially maintained under a one-response fixed-ratio schedule which delivered single food pellets (0.045 g, Noyes). With the clear lucite Model C chamber, lever pressing of experimental animals (n = 5) was maintained in the presence of a clicking noise and a white light mounted over the lever, and nose-key pressing was maintained in the presence of a tone noise and a white light mounted behind the nose-key (multiple schedule). After initial training, the response requirement was gradually increased to 30, and schedule com- ponents alternated every 20 reinforcers or 10 rain, whichever oc- curred first. Daily sessions at 7:00 a.m. lasted for three exposures of each component (approximately 60 min). With the smaller clear lucite chamber, lever pressing of the same animals was maintained in the presence of a clicking noise and a white light mounted over the lever (individual schedule). After initial training, the response requirement was gradually increased to 30, and daily sessions at 1:00 p.m. lasted for 60 min. Animals responded under these con- ditions until variability of response rate for each schedule was within 20% lbr 2 successive weeks. This procedure is depicted in Fig. 1.

Env i ronment - - _1_ FR30 (Lev) __ ~. FR30 (Key) 0700 hrs

C B

Phencyc l id ine

- 2 -

FR30 (Lev) 1300 hrs

A

Admin is t ra t ion

Fig. 1. Depiction of the multi-environment procedure for experi- ment 2. Lever and nose-key pressing were separately maintained under a multiple FR30 schedule during the first daily session in one chamber, and lever pressing was maintained under an individual FR30 schedule during the second daily session. Some animals (n = 5) experienced both sessions in the same experimental chamber, and other animals (n = 5) experienced each session in different ex- perimental chambers. Phencyclidine was administered at times A, B, or C during the course of the experiment. Effects of chronic administration at times B and C correspond to effects shown in panels B and C of Figs. 3 and 4

Control animals (n = 5) responded under the same schedule and manipulanda conditions twice daily in the same clear lucite Model C chamber. Lever pressing and nose-key pressing were maintained at 9:00 a.m. under a multiple schedule, and lever pressing was maintained at 3:00 p.m. under an individual schedule.

Drug procedure. Acute administration of phencyclidine was the same as in experiment 1. Drug was dissolved in a 0.9% sodium chloride solution and injected IM in a volume of 0.5 ml/kg body weight. Similar volumes of vehicle served as control injections. After initial training and development of stable performance, each animal received at least five injections of each of several doses of phencyclidine (0.3-3.0 mg/kg) once weekly in mixed order im- mediately prior to each experimental session. When animals received phencyclidine prior to the first session (Fig. 1, condition C), they were not studied on that day in the second session (Fig. 1, condition B). Each animal also received at least seven injections of vehicle once weekly immediately prior to each experimental session, and the average of these sessions was used for comparing pre-drug control responding with effects of both acutely and chronically administered phencyclidine.

After determination of acute dose-effects using the same general procedure described for experiment 1, animals received 3.0 mg/kg/day phencyclidine for 4 weeks at each of the following times: after the individual schedule in the second session (Fig. 1, Condition A); before the individual schedule in the second session (Fig. 1, condition B); and then before the multiple schedule in the first session (Fig. 1, condition C).

Resuhs

Experiment 1

Control responding. Behavior was readily control led un- der both DRL and Time-Delay schedules in separate experimental chambers, and rates and patterns of both responding and food delivery were comparable to those commonly reported for similar schedules and parameters presented individually (Smith 1986; Hi l tunen et al. 1989). Lever pressing under the DRL schedule occurred at

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~3 ~2

P,

Pheneyel id ine (3 mg/kg /day)

A B Acute

Administration

DRL T /~

0.3 1.0 1.7 s.o 1 5 Dose (mg/kg}

C Before Time-Delay Before DRL

Second Session First Session

Fig. 2. Effects of acute (Panel A) and repeated daily administration (PaneLs B-D) of phencyclidine on responses/m (+ 1 SD) under Time-Delay (filled circles; control X = 2.01 :k 0.09) and DRL (open circles; control X = 1.36 :t: 0.23) schedules. Phencyclidine (3,0 rag/ kg) was administered after responding of both sessions (not shown); before Time-Delay responding of the second session (Panel B); before DRL responding of the first session (panel C); and before Time-Delay responding of the second session (panel D). During drug administration shown in panel D, phencyclidine was adminis- tered twice before the first session (marked by an asterisk). Response

Spaced-Respond ing

D Before Time-Delay

Second Session

10 15 20 25 30

Blocks of Two Sessions

rate was compared for selected sessions of each panel, and t-tests for dependent-samples verified visual inspection. Time-delay re- sponding during session 1 (filled circles panel B) was the same as for acutely administered 3 mg/kg [t(4)=0.319]; DRL responding during session 11 (open circles, panel C) was the same as for acutely administered 3 mg/kg [t(4)= 1.37]; and DRL responding during sessions 24 and 29 (open circles marked by asterisks, panel D) was higher than DRL responding during sessions 23 and 2 respectively [t(4)=3.15, P

125

Phencyclidine (3 mg/kg/day) Different Environment

1.25

A Acute

Administration

B Before

Individual Schedule

C Before

Multiple Schedule

1.00 44

0.75 0

CO

0.50

g

0.25 t'r"

p '-~ ,~i,,. I "~

0.3 1.0 1.7 3,0 5 10

Dose (mg/kg) Blocks of

Fig. 3. Effects of acute (panel A) and repeated daily administration (panel B and C) of phencyclidine on responses/s ( t SD) under an FR30 schedule of lbod presentation. Squares are for a multiple schedule at 7: 00 a.m, with nose-key pressing (filled points; control X=0.890.12) and lever pressing (open points; control X=0.650.08), The open circle is for an individual schedule of lever pressing in a different experimental enviroment at 1 : 00 p.m. (control ~=0.81 0.09). Phencyclidine (3.0 mg/kg) was adminis- tered after responding of both sessions (not shown); before lever responding during the afternoon session with an individual schedule

15 20

Two Sessions

(panel B); and before responding on both manipulanda during the morning session with the multiple schedule (panel C). Response rate was compared for selected sessions of each panel, and t-tests for dependent-samples verified visual inspection. Responding on both manipulanda during session 11 of the multiple schedule (squares, panel C) was no different than that after acutely administered 3 mg/kg phencyclidine [t(4)=0.064 nose-key; t(4)=0.206 lever]. Lever responding during session 11 of the individual schedule (open circles, panel C) was no different than during vehicle control con- ditions [t(4)= 1.24]

Phencyc l id ine (3 mg/kg /day) Same Env i ronment

1.25

a co 1.oo 44 "1o

o 0.75 0 D

Cq

0.50 u~

0 c~

O,25 r

A Acute

Administration

I Key Mult

Do Lev Molt Lev lndiv

0.3 i t i

1.0 1.7 3.0

B Before

Individual Schedule

5 10

Dose (rng/kg) Blocks of

Fig. 4. Effects of acute (panel A) and repeated daily administration (panets B and C) of phencyclidine on responses/s ( 1 SD) under an FR30 schedule of food presentation. Squares are for a multiple schedule at 9:00 a.m. with nose-key pressing (filled points; control R = 0.96 :t: 0.10) and lever pressing (open points; control X = 0.82 0,11). The open circle is for an individual schedule of lever pressing in the same experimental environment at 3:00 p.m. (control R = 0.74 :t: 0.09). Phencyclidine (3.0 mg/kg) was administered after responding of both sessions (not shown); before lever responding during the afternoon session with an individual schedule (panel B);

C Before

Multiple Schedule

15 20

TWO Sessions

and before responding on both manipulanda during the morning session with the multiple schedule (panel C). Response rate was compared for selected sessions of each panel, and t-tests for depen- dent-samples verified visual inspection. Responding on both ma- nipulanda during session 11 of the multiple schedule (squares, panel C) was greater than that after acutely administered 3 mg/kg phency- clidine It(4)= 15.25 nose-key; t(4)= 8.47 lever], although it was less than that during session 10 (panel B) when animals last received phencyclidine after multiple-schedule sessions It(4) = 11.8 nose-key; t(4) = 3.54 lever]

126

multiple schedules. Lever pressing during the individual schedule occurred at 0.66-0.84 responses per second and animals received 75-100 reinforcers per session. Lever pressing during the multiple schedule occurred at 0.57-0.88 responses per second and animals received 32-56 reinforcers per session in that component. Nose- key pressing during the multiple schedule occurred at 0.78-1.15 responses per second and animals received 44-67 reinforcers per session in that component.

Acute drug effects. FR responding on both manipulanda was decreased as dose of phencyclidine increased for individual and multiple schedules occurring in both dif- ferent (Fig. 3A), and the same environmental circum- stances (Fig. 4A).

Chronic drug effects. Responding was not affected for either schedule when 3.0 mg/kg/day phencyclidine was administered for 4 weeks after the second daily session (Fig. 1, Condition A; data not shown in Figs. 3 and 4). When phencyclidine was then given before FR lever re- sponding in the second daily session (Fig. 1, condition B), that responding was initially decreased just as it had been when phencyclidine was given acutely (Figs. 3B and 4B, open circles). As phencyclidine continued to be adminis- tered before lever responding of the individual schedule, however, tolerance developed to increased responding within approximately 4 weeks. Consequently, pharma- cologic effects of 3.0 mg/kg/day phencyclidine for 4 weeks after both sessions did not result in significant tolerance to its behavioral effects on FR lever perfor- mance, but marked tolerance did develop when drug administration preceded that performance.

There were no effects on FR responding in the multi- ple schedule during the first daily session for either group throughout the period of phencyclidine injections prior to the second daily session with the individual schedule (Figs. 3B and 4B, squares). However, there were marked- ly different effects for the two groups when phencyclidine was given immediately before FR responding in the mul- tiple schedule (Fig. 1, condition C). For experimental animals experiencing the individual and multiple schedules in different environmental circumstances, FR responding on both manipulanda of the multiple schedule were markedly decreased when phencyclidine first preceded multiple schedule responding (Fig. 3C, squares). This indicates that tolerance which had de- veloped for other behavioral effects of phencyclidine during 8 weeks of drug administration for these animals did not generalize significantly to their effects on FR responding in the multiple schedule. In contrast, initial effects of phencyclidine on responding in the multiple schedule were not as great for control animals experienc- ing both individual and multiple schedules in the same environment (Fig. 4C, squares). This indicates that tolerance which had developed for other behavioral effects of phencyclidine during 8 weeks of drug ad- ministration for these animals did partially generalize to their FR responding in the multiple schedule. Thus, characteristics of the environmental apparatus were corn-

paratively more influential on tolerance generalization than were differences for schedule context or manipulanda.

Discussion

Responding was readily controlled and maintained in two different environmental situations by spaced- responding (experiment 1) and fixed-ratio (experiment 2) schedules of food presentation, and rates and patterns of performance were comparable to those commonly re- ported for similar schedules and parameters when presented individually. These effects on DRL responding are similar to those reported previously for rats' lever pressing under DRL schedules of food delivery (Poling et al. 1981 ; Sanger and Jackson 1989) and mice respond- ing under a DRL schedule of sweetened milk presenta- tion (Balster and Baird 1979). The present results are the first we are aware of for rate-decreasing effects of phency- clidine on spaced-responding maintained under a Time- Delay schedule, and they suggest that contingencies of reinforcement for the two schedules are more influential on the behavioral effects of phencyclidine than a puta- tively common "timing process".

Responding under the FR schedule was decreased as dose of phencyclidine increased to 3.0 mg/kg. These effects are similar to those reported previously for rats (Poling et al. 1981; Beardsley and Balster 1987), and squirrel monkeys (Chait and Balster 1978) responding under an FR schedule of food presentation and for mice responding under an FR schedule of milk delivery (Wen- ger and Dews 1976). Segal et al. (1981) reported in- creased FR lever pressing by phencyclidine in rats, but inspection of their cumulative records suggests that their observed increase in FR responding may have resulted from elimination of post-food pausing instead of in- creased responding per se.

When animals in the present experiment received daily injections of 3.0 mg/kg phencyclidine, tolerance to behavioral effects of drug developed only in the presence of environmental stimuli that were coincident with pharmacologic effects of the drug. Tolerance did not develop to behavioral effects on responding under any schedule studied when injections occurred after the last daily session and therefore outside all behavior procedures. These effects of post-session drug ad- ministration have been previously reported for a number of drugs and schedule-conditions, and they support the general conclusion that tolerance to unspecified behav- ioral effects occurring outside observed experimental conditions does not necessarily generalize to perfor- mance characteristics measured under experimental cir- cumstances (Siegel 1976; Murray et al. 1977; Smith 1979; Woolverton and Balster 1979). In addition, how- ever, the present results show that tolerance following repeated daily administration of phencyclidine in the presence of one set of specified behavioral procedures did not extend to behavioral effects of phencyclidine on re- sponding under either similar or dissimilar procedures occurring in different specified environmental circum-

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stances. Tolerance to effects of phencyclidine on Time- Delay responding in one chamber did not extend to effects o f phencyclidine on DRL responding in a different chamber, for example, and tolerance to effects of phency- clidine on FR responding did not extend to even the same manipulandum in a different chamber. In contrast, tolerance that developed to effects o f phencyclidine on FR responding did extend to performance on even a different manipu landum in a different schedule context when these other conditions occurred in the same experi- mental chamber. These effects are consistent with results reported for both rat (Greeley and Cappell 1985; Smith 1990a,b) and human (Shapiro and Nathan 1986) under similar mult i -environment procedures. It is not evident from the present procedure, of course, whether the over- riding influence of physical environment also occurs when reinforcement contingencies and response topo- graphies are more markedly different than those studied here, and ongoing experiments are studying these addi- tional variables.

A singular effect of a drug is not an inevitable conse- quence of its acute administration (Morse et al. 1977; Chrusciel 1978; McKearney 1979; Barrett t 985; Brady and Barrett 1986), and tolerance to effects of a drug is not an inevitable consequence of its chronic administration (Peele 1981; Barrett et al. 1989; Blackman 1989; Smith 1990a, b). Using environmental circumstances associated with different experimental chambers, the present experi- ment has continued to identify behavioral manipulat ions which can influence tolerance to the behavioral effects of drugs.

Acknowledgements. This research was supported by USPHS Grant DA01987. I thank J.W. McKearney for comments on an earlier form of the manuscript and V. DeStratis for technical assistance.

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