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616

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Copyright © 1976 by The Williams & Wilkins Co.Vol. 196, No. 3

Printed in U.S.A.

THE EFFECTS OF PHENCYCLIDINE, KETAMINE,

d-AMPHETAMINE AND PENTOBARBITAL ON

SCHEDULE-CONTROLLED BEHAVIOR IN

THE MOUSE” 2

GALEN R. WENGER AND P. B. DEWS

Laboratory of Psychobiology, Harvard Medical School, Boston, Massachusetts

Accepted for publication October 20, 1975

ABSTRACT

WENGER, GALEN R. AND P.B. DEWS: The effects of phencyclidine, ketamine,

d-amphetamine and pentobarbital on schedule-controlled behavior in the mouse.

J. Pharmacol. Exp. Ther. 196: 616-624, 1976.

The response of mice of breaking a light beam onto a photocell was programmed to

produce food according to a multiple schedule with alternating 30-response fixed ratio,

300-second fixed interval (FR-30 FI-300 sec) components. Training was standardized

for all mice, and stable patterns of responding that were similar to those described for

other species and responses under this schedule developed quickly. The effects of

pentobarbital, d-amphetamine, phencyclidine and ketamine were studied. At some

dose, each of the four drugs produced an increase in rate of responding; the increase was

proportionately greater at low rates of responding than at higher rates. At some dose

range, d-amphetamine, ketamine and phencyclidine produced dose-related increases

in Fl response rates but only decreases in FR response rates. The maximum increases in

Fl average rates were to 1.83, 1.25 and 1.32 times the control rate for d-amphetamine (1

mg/kg), ketamine (100 mg/kg) and phencyclidine (3 mg/kg), respectively. Phencycli-

dine and ketamine thus showed some “amphetamine-like” effects in the mouse.

Pentobarbital increased (1.25 times the control rate) both the FR and Fl response rates

at a dose of 3 mg/kg. Higher doses of pentobarbital progressively decreased both FR

and Fl response rates in a parallel fashion.

Phencyclidine hydrochloride (PCD) and ke-

tamine hydrochloride (KT) can change the

behavior of laboratory animals at subanesthetic

doses. Increases in spontaneous locomotor ac-

tivity are observed in mice and rats after low

Received for publication June 16, 1975.

‘This investigation was supported by U.S. PublicHealth Service Grants MH 07084, MH 02094, MH07658 and MH 00499.

2A preliminary abstract of the study appears inFed. Proc. (34: 766Abs, 1975).

doses of PCD or KT (Chen et a!., 1959, 1966;

Hittzemann et a!., 1973), an effect that is

enhanced by pretreatment with iproniazid

(Chen et a!., 1965). The same studies report a

“calming” effect in pigeons, guinea pigs, ham-

sters, cats, dogs and monkeys after low doses of

PCD or KT and a state of immobility at higher

doses.

At present, there is little information on the

effect of PCD or KT on schedule-controlled

(operant) behavior. Previous work in this labo-

ratory (Wenger, 1976) has shown PCD and KT

to have effects qualitatively like those of am-

phetamine on a multiple schedule of food pres-

1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 617

FIG. 1. A diagram of the experimental chamber used for mice (see text for further details).

entation in the pigeon, with alternating 30-

response fixed ratio and 600-second fixed inter-

val (FR-30, FI-600 sec) components. PCD has

also been shown to have effects similar to those

of amphetamine on Fl performance in the

squirrel monkey (L. Byrd, personal communica-

tion).

The purpose of the present study was to

determine the effects of PCD and KT on re-

sponding under a mult FR-30 FI-300 sec sched-

ule of food presentation in the mouse. This

schedule was adopted because it has proved

useful in determining drug effects in other

species. Consequently comparison of the mouse

with other species could be made in order to

assess the usefulness of the mouse in behavioral

pharmacology. To aid in this assessment, d-

amphetamine and pentobarbital, which have

been extensively studied in other species, were

studied as reference drugs. The patterns of

responding observed in the mouse on the mult

TOP VIEW

SIDE VIEW

FR-30 FI-300 sec schedule were similar to those

observed with other species and other responses

under this schedule of reinforcement. The ef-

fects of d-amphetamine, PCD and KT in the

mouse were similar to the effects in the pigeon,

whereas there were differences in the effects of

pentobarbital.

Methods

Subjects. Male C57BL type mice derived from aC57BL/6J strain were used. They weighed approxi-mately 30 g when given free access to food and water.

Throughout the experiment they were maintained at75% of their free feeding weight. None of the mice had

been previously trained. Six mice (designatedM-47 to M-52) were used in the PCD study, three

mice (designated M-67 to M-69) in the KT study, andtwo mice each in the pentobarbital and d-ampheta-

mine studies (designated M-59, M-60 and M-61,M-62, respectively). The mice were housed in the

open laboratory, and testing was conducted during

the normal working day.

MICE

618 WENGER AND DEWS Vol. 196

Apparatus. The experimental chamber was a mod-

ified polypropylene mouse cage measuring 18 cm x 28

cm x 12 cm high (fig. 1). At one end ofthe chamber a

partition was installed creating a blind corridor 3.5cm wide and 5 cm long. At a point 0.5 cm from the endof the corridor a photocell was installed 1.2 cm from

the floor of the chamber in one of the side walls of the

corridor. At the corresponding point in the oppositewall a light source was mounted so that a beam of

light crossed the width of the corridor to strike thephotocell. An interruption of the light beam to the

photocell was recorded as a response. Directly below

the light beam was an opening in the floor (1 cm in

diameter) through which the mouse was given 3-

second access to a 0.025 ml dipper of evaporated milk.

On the wall at the end of the corridor at a point 4 cm

from the floor, a translucent plastic circle 1.2 cm in

diameter was mounted as a stimulus panel. The circlewas transilluminated by a 7.5 w green bulb during the

appropriate schedule component. In addition, an

electromechanical relay was installed on the side ofthe chamber which was operated four times per

second to make a clicking noise during the appropri-

ate schedule component. A second relay, operated

on interruption of the photocell beam, producedauditory feedback for each response. The experimen-

tal chamber was placed inside a sound attenuatingchamber; a 7.5 w bulb, in series with a 1000 ohm

resistor, illuminated the chamber at all times except

during the dipper presentation, producing a very low

level of illumination. Standard relay programmingand recording apparatus were used.

Procedure. A multiple FR-30 FI-300 sec schedule

of food presentation has been described in detail by

Ferster and Skinner (1957). In addition, Dews and

Morse (1958) and Morse (1962) have discussed the

application of the schedule to behavioral pharmacol-

ogy. In the presence of a distinctive stimulus, thegreen light in this experiment, 30 responses resulted in

access to the dipper of evaporated milk (FR-30). In

the presence of a different stimulus, the clicking relay

in this experiment, responding was maintained byaccess to the dipper of evaporated milk upon a

response at the end of the 300-second interval

(FI-300 sec). The schedules and their associatedstimuli alternated throughout the session. If 30 re-

sponses were not completed within 120 second in the

presence of the green light (FR), the schedule

changed; the light was turned off, and the clickingrelay started (Fl). If no response occurred within 30second after the 300-second interval had elapsed, theschedule changed back to FR. The session terminated

after 20 component changes had occurred (about 50

minute).

Training. Training was standardized for all mice,

and no manual shaping of the response was requiredon the part of the experimenter. The mouse wasdeprived of food until a body weight equivalent to 75%

of the free feeding weight was obtained. Typically the

desired weight loss was achieved in 2 to 3 days of fooddeprivation. The mouse was placed in the experimen-

tal chamber with a FR-i schedule in effect; a singleinterruption of the light beam onto the photocell

produced access to a dipper of evaporated milk. For

the first session, the dipper remained in the upposition for 10 second; in subsequent sessions the

dipper remained in the up position for only 3 second.Over the next 3 days, the FR response requirementwas increased to FR-30, and high rates (> 1.0 re-

sponses/sec) were maintained at each FR value. On

day 5, a mult FR-30 FI-300 sec schedule of food pres-entation was in effect. Stable performance wasachieved after about 12 sessions under this schedule

of food presentation.

Drugs. The drugs used were phencyclidine hydro-

chloride (Sernylan, BioCeutics Laboratories, St. Jo-

seph, Mo.), ketamine hydrochloride (Vetalar, Parke,

Davis and Company, Detroit, Mich.), pentobarbitalsodium (Abbott Laboratories, North Chicago, Ill.)

and d-amphetamine sulfate (Smith, Kline andFrench Laboratories, Philadelphia, Pa.). Phencycli-

dine hydrochloride and ketamine hydrochloride were

diluted with saline to the appropriate concentration.Pentobarbital sodium and d-amphetamine sulfate

wI-

LiJ��cr

crz

0

mg/kg d-AMPHETAMINE

FIG. 2. Effect ofd-amphetamine on the average rateof responding in each component of the mult FR-30FI-300 sec schedule. Abscissa: dose in milligrams perkilogram of body weight on a log scale; ordinate: ratioof the average rate after drug administration to theaverage rate on nondrug control days. Vertical lines atC represent the mean plus or minus 2 standard errorsof the control. The solid horizontal line represents themean control value. Each point represents the meanof single determinations in each of two mice. Meancontrol rates of responding were 0.62 responses/secand 1.40 responses/sec for the F! and FR, respectively.

M-61 M-6O

CONTROL

U)LiiC,)

a.U)Lii

000

30 mg/kg PENTOBARBITAL

V/v�

1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 619

were dissolved in saline. All drug concentrations were

made so that the desired dose could be given in a

volume of 1 ml/100 g b.wt. All drugs were adminis-

tered by i.p. injection 300 second before the beginning

of the session; all doses are expressed as the salt. The

dose ranges studied were: PCD, 0.3 to 30 mg/kg i.p.

(1.25-125 ��mol/kg); KT, 1 to 180 mg/kg i.p.

(3.68-662.4 �mol/kg); d-amphetamine, 0.1 to 30mg/kg i.p. (0.27-81 �tmol/kg); and pentobarbital, 1 to

30 mg/kg i.p. (4.03-226 �smol/kg).

Drug injections were made once per week; the datacollected on the previous day served as the noninjec-

tion control.Measurement of drug effects. Average rates of

responding were computed as responses per secondfrom digital counters and elapsed time meters sepa-

rately for the FR and F! components. Results are

expressed as a ratio of the rate of responding on drugdays to the rate of responding on control days. For

analysis of rate dependencies, the Fl was divided into

10 equal segments. The responses in correspondingsegments of each interval were accumulated for theentire session, and a mean rate of responding wasdetermined for each segment. In addition, the meanrate of responding in the FR component was calculat-

ed. The mean rate of responding in each segment of

the F! and the mean rate of the FR on drug days were

expressed as a ratio of the response rate after drugadministration to the control rate in the correspond-

ing segment of the Fl and the FR. The ratio was

plotted on a log-log plot as a function of the control

rate of responding (Dews, 1964).

Results

The mult FR-30 FI-300 sec schedule engen-

dered patterns of responding similar to those

seen with other responses in other species

(Ferster and Skinner, 1957; Dews, 1955). Per-

formance in the FR component is characterized

by a very short initial pause averaging 1.7

second, followered by a continuous rate of

responding at more than 1.5 responses/sec.

Performance in the Fl component comprised an

initial pause much longer than under the FR,

followed by gradually accelerating responding

until the presentation of the food. Mean rate of

responding in the Fl was 0.73 responses/sec.

d-Amphetamine produced a dose-related de-

CONTROL

3 mg/kg �-AMPHETAMlNE

�

10 mg/kg g-AMPHETAMINE

600 SECONDS

FIG. 3. Cumulative response records of the performance of mice M-6i and M-60 under the mult FR-30 FI-300sec schedule showing typical control performances, the effect of two doses of d-amphetamine and two doses ofpentobarbital. Diagonal marks on the response pen line indicate the presentation of evaporated milk.Downward deflections of the lower horizonal line indicate the occurrence of the FR component of the multipleschedule. The pen automatically resets after 1000 responses and at the end of the session.

WENGER AND DEWS Vol.196

I 50

25

MICE

Li

LiJ�

0

0.75

0.50#{149} #{149}F1300

0---�0 FR3O

0.25

\

620

crease in FR response rates, and a biphasic

effect (increase at low doses and decrease at

high doses) on Fl response rates (fig. 2). The

response rate in the FR component was de-

creased at lower doses than those necessary to

decrease average Fl response rate.

The effect of two doses of d-amphetamine on

the performance of one mouse (M-6i) is seen in

the representative cumulative response records

shown in figure 3. The most striking feature

observed was the large increase in the Fl re-

sponse rate, especially in the early portions of

the Fl. The drug-induced changes in Fl re-

sponding were dependent on the control rate of

responding: low rates were increased more than

high rates. By inspection of the cumulative

record, at 10 mg/kg the rate of responding

during the period of FR responding was de-

creased with no obvious change in the pause

before the start of the FR responding.

The effects of pentobarbital on both FR-30

and FI-300 sec performances were dose depend-

ent (fig. 4) and both components were similarly

affected; response rates were increased at low

doses and decreased at high doses. The dose

producing the maximum increase in Fl respond-

LiLii�

0

0 - __C NaCI 0.3 I 3 0 1 30

8

mg/kg PHENCYCLIDINE HCI

.50

MICE MICE

#{149} #{149}F1300

0-- -o FR 30

to0

C I 3 013018 56mg/kg PENTOBARBITAL

C I 3 0 30H00156 180

mg/kg KETAMINE - HCI

FIG. 4. Effect of pentobarbital on the average rate ofresponding in each component of the mult FR-30F1-300 sec schedule. The data are expressed as infigure 2. Each point represents the mean of singledeterminations in each of two mice. Mean controlrates of responding were 0.82 responses/sec and 1.48responses/sec for the F! and FR, respectively.

FIG. 5. Effects of PCD on the average rate ofresponding in each component of mult FR-30 FI-300sec schedule. The data are expressed as in figure 2.Each point represents the mean of single determina-tions in each of six mice. Mean control rates ofresponding were 0.74 responses/sec and 1.43 re-sponses/sec for the Fl and FR, respectively.

FIG. 6. Effects of KT on the average rate ofresponding in each component of the mult FR-30FI-300 sec schedule. The data are expressed as infigure 2. Each point represents the mean of singledeterminations in each of three mice. Mean controlrates of responding were 0.68 responses/sec and 1.60responses/sec for the F! and FR, respectively.

M-49 M-69

CONTROL

U)wU)z0a.U)Lii

000

30 mg/kg KETAMINE

100 mg/kg KETAMINE

A A

/� /1 �11

1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 621

CONTROL

VVH10 mg/kg PHENCYCLIDINE

8 mg/kg PHENCYCLIDINE

:1

600 SECONDS

FIG. 7. Cumulative response records of the performance of mice M-49 and M-69 under the mult FR-30 FI-300sec schedule showing typical control performances, the effect of two doses of PCD and two doses of KT.Diagonal marks on the response pen line indicate the presentation of evaporated milk. Downward deflections ofthe lower horizontal line indicate the occurrence of the FR component of the multiple schedule. The penautomatically resets after 1000 responses.

ing also produced the maximum increase in FR

responding.

In figure 3 representative cumulative records

are also shown for one mouse (M-60), showing

control and two doses of pentobarbital. Pento-

barbital had a marked effect on the F! pattern

of responding. Responding in early portions of

the Fl was increased more than responding in

the terminal portions, resulting in a more nearly

constant response rate in the Fl component at

doses of 3 mg/kg and higher, at the time of peak

effect. The changes in the rate of responding

induced by the drug were rate-dependent in

that low rates were increased proportionately

more than high rates. At the highest dose

studied, 56 mg/kg, not shown, responding was

completely suppressed for most of t�ie session.

When responding started, the effect of pento-

barbital appeared to be the same in both

components.

PCD had qualitatively similar effects to KT

on the responding maintained by the mult

FR-30 FI-300 sec schedule (figs. 5 and 6). Both

produced a dose-related decrease in responding

in the FR component. The doses of PCD and

KT which decreased response rates in the FR

component were lower than the doses required

to decrease average Fl response rates. The effect

of PCD and KT on the Fl response rate was

biphasic. At low doses the Fl response rate was

increased, and at higher doses the Fl response

rate was decreased.

Figure 7 shows representative cumulative

records of responding in two mice under con-

trol conditions and after two doses of PCD or

two doses of KT. The effect of PCD and KT

on the F! component is to increase responding in

the early portions of the Fl. This produces the

nearly constant rate of responding observed at

the time of peak effect with 10 mg/kg of PCD

and at 30 mg/kg of KT. The mean rate of

responding under the FR component is de-

creased by PCD and KT without an apparent

increase in pause time before the start of the FR

responding.

That the effect of PCD and KT on Fl re-

sponding is dependent on the corresponding

control rate of responding is seen in figures 8

and 9. With PCD (fig. 8), low control rates of

responding are increased while higher control

00

#{163}

622 WENGER AND DEWS Vol.196

10.0

Lii 3.0‘Li4

00

0

0.3

M -48

PHENCYCLI DINE

0-o 3 mg/kg

#{149} #{149}10 mg/kg

M-49

0 -‘

0.1 0.3 1.0 3.0 0.1 0.3 1.0 3.0

CONTROL RATE CONTROL RATE

FIG. 8. Dependence of the effect of PCD on the control rate of responding in mice M-48 and M-49. Abscissa:average rate of responding on a log scale in successive 30-second periods of the F!-300 sec schedule (circles), andunder the FR-30 response schedule (triangles); ordinate: ratio of the average rate after drug administration tothe average rate on nondrug control days. Open symbols (circles and triangles) represent the effect of 3 mg/kgi.p. of PCD; closed symbols represent the effect of 10 mg/kg i.p. of PCD.

rates of responding are either unchanged (3

mg/kg) or, as seen at 10 mg/kg, decreased. The

same qualitative relationship is seen with KT

(fig. 9). Figures 8 and 9 show also that the points

for the FR performance lie below the regression

line of rate dependence drawn through the F!

data points.

Discussion

Interruption of a light beam striking a photo-

cell is a response easily acquired by mice

without the necessity of individual “shaping”

by the experimenter. Training can thus be

standardized. Also, the large numbers of sub-

jects necessary for some lines of work could be

trained without the labor becoming prohibitive.

Stable performance is achieved rapidly on a

schedule such as mult FR-30 FI-300 sec, and the

pattern of responding is very similar to other

species and other responses. The behavior

maintained by the mult FR-30 FI-300 sec sched-

ule in the mouse rapidly comes under stimulus

and schedule control, as seen in the cumulative

records.

The effects of d-amphetamine on the behav-

ior of the mouse are similar to the effects

reported for other species responding on similar

schedules. d-Amphetamine produced a dose-re-

lated decrease in the FR response rate, and

a biphasic (increase followed by a decrease)

effect on response rates in the Fl. The FR

behavior appeared to be more sensitive to the

rate decreasing effects of d-amphetamine than

did the Fl behavior. In addition, the rate

increases seen in the Fl were of the rate-depend-

ent type: low rates were increased more than

high rates. These effects are similar to the

effects of d-amphetamine on pigeons pecking a

pigeon key (Smith, 1964; Rutledge and Kelle-

her, 1965; McMillan, 1968, 1969), rats pressing

a lever (Clark and Steele, 1966) and monkeys

pressing a lever (Cook and Kelleher, 1962;

Kelleher and Morse, 1964).

The effect of pentobarbital on the perform-

ance of mice on this schedule is similar to that

reported for barbiturates in pigeons (Rutledge

and Kelleher, 1965; Morse, 1962; Leander and

McMillan, 1974; McKearney, 1972) and mon-

1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 623

M-67 M-68

KETAMINE

0-o 30 mg/kg

#{149}#{149}56 mg/kg

0.0

3.0

0

.0

0.3

#{163}

00.1 0.3 1.0 3.0 0.1 0:3 .0 3.0

CONTROL RATE CONTROL RATE

FIG. 9. Dependence of the effect of KT on the control rate of responding in mice M-67 and M-68. The data areexpressed as in figure 8. Open symbols (circles and triangles) represent the effect of 30 mg/kg i.p. of KT; closedsymbols represent the effect of 56 mg/kg i.p. of KT.

keys (Verhave, 1959) on multiple Fl FR

schedules, except that the greater sensitivity of

F! over FR in responding to the rate-decreasing

effects of the barbiturates was not observed.

The behavioral effects of PCD and KT are

similar to those seen recently in the pigeon

(Wenger, 1976). Both drugs produced a biphasic

(increase followed by decrease) effect on the Fl

response rate. The amount of increase or de-

crease in rate depended on the control rate of

responding: low rates of responding were in-

creased more than high rates of responding. The

behavior maintained by the FR component in

the mouse was decreased by both PCD and KT

in a dose-related manner. The FR rate was

decreased more than would have been predicted

on the basis of the changes produced by the

drug in Fl responding (figs. 8 and 9). The

different effects of the drugs on responding

under the FR and under the Fl were not

exclusively dependent on the average rate of

responding.

PCD and KT increased responding main-

tamed by the F! component at doses which

decreased the responding maintained by the FR

(figs. 5 and 6). The maximum increase in Fl

response rates occurs at a dose of d-ampheta-

mine which does not affect the average FR

response rate (fig. 2). Pentobarbital produces a

maximum increase in F! response rates at the

same dose which produces the maximum in-

crease in the FR response rates (fig. 4). These

differences appear to be drug-specific effects.

PCD, KT and d-amphetamine increase spon-

taneous motor activity as measured by jiggle

cages (Schulte et a!., 1941; Chen et a!., 1959,

1966). More recent work counting photocell

crossings has confirmed the earlier results

(Smith, 1963; Rolinski and Scheel-Kr#{252}ger, 1973;

Villarreal et al., 1973; Thornburg and Moore,

1973; Glick and Milloy, 1973; Hittzemann et al.,

1973). Although the response used in this study

was also the breaking of a light beam striking a

photocell, the dose-response relationships are

different from those seen with “spontaneous”

motor activity. Hittzemann et a!. (1973) re-

ported a dose-dependent increase in motor ac-

tivity in mice given PCD with a maximum

increase at 10 to 30 mg/kg i.p. In the present

study, the maximum increase in the response

rate in the F! component was observed after 3

mg/kg i.p. PCD. Doses higher than 3 mg/kg of

624 WENGER AND DEWS Vol.196

PCD decreased the schedule-controlled re-

sponse rate. Similarly, d-amphetamine pro-

duces dose-related increases in motor activity

with the maximum effect observed at 5 to 10

mg/kg i.p. (Smith, 1963; Rolinski and Scheel-

Kruger, 1973; Villarreal et a!., 1973; Thronburg

and Moore, 1973; Glick and Milloy, 1973; Hitt-

zemann et a!., 1973) which is also higher than

the dose of d-amphetamine producing the max-

imum increase in F! responding in the present

study.

In summary, PCD and KT have been shown

to have very similar effects in the mouse on a

mult FR F! schedule of food presentation. The

effects are generally similar to those seen in the

pigeon. The effects of d-amphetamine are also

similar to those reported in a variety of other

species on similar schedules; pentobarbital

showed differences in that F! and FR respond-

ings were similarly affected, but more work is

necessary to determine whether the difference is

due to species differences, response differences

or other factors.

Acknowledgments. The authors would like

to thank Drs. W. H. Morse and R. T. Kelleher

for helpful comments and Margery Schwartz

and Carolyn Mosher for help in the preparation

of this manuscript.

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