Effect of repeated haloperidol administration on phencyclidine discrimination in rats

Fmg. P?ew.-Psychopf~macot

& BfnL Psychtat Copyright

Pergamon

Plinted

1995, Vol.19.pp.699-711 0 1995 Ekxier Science Ltd

in Great Britain.

All rights reserved

027.%5646/95

0278-5846(95)00113-A EFFECT OF REPEATED HALOPERIDOL ADMINISTRATION PHENCYCLIDINE DISCRIMINATION IN RATS

ON

JENNY L. WILEY Department of Pharmacology & Toxicology Virginia Commonwealth University Medical College of Virginia Richmond, VA U.S.A.

(Final form, October

1994)

Abstract Wiley! Jenny L.: Effects of repeated haloperidol administration on phencyclidine & Biol. Psychiat .1995, 19(4): discrimination in rats. Prog. Neuro-Psychopharmacol. 699-711.

1.

Previous research has shown that acute doses of haloperidol block many of themotor stimulatory effects of phencyclidine (PCP) and other PCP-like produces partial In addition, when given acutely, haloperidol drugs. attenuation of PCP's discriminative stimulus effects in rats.

2.

Haloperidol is often administered chronically in clinical situations; hence, it is important to investigate the effects of repeated, as well as acute, dosing with this drug.

3.

The purpose of the present study was to examine the effects of repeated Rats were administration of haloperidol on PCP discrimination in rats. trained to discriminate PCP (2.0 mg/kg) from saline in a two-lever drug discrimination procedure and were testedwith cumulative doses of PCP before and after repeated administration of saline and of haloperidol (0.5 mg/kg/day).

4.

Discrimination training was suspended during the two 14-15-day repeated dosing regimens. Suspendedtrainingwith repeated saline administrationhad little effect on the dose-effect curve for % PCP-lever responding.

5.

Repeated administration of haloperidol produced some diminution of PCP discrimination. After haloperidol, the ED,, for % PCP-lever responding was 1.4 mg/kg, compared to the pre-haloperidol ED,, of 0.7 mg/kg.

6.

These results are consistent with those of acute dosing studies with haloperidol in PCP-trained rats and suggest that repeated administration of haloperidolmay disrupt PCP's discriminative stimulus effects, althoughmost rats were still able to discriminate the higher doses of PCP.

Kevwords:

drug discrimination,

haloperidol,

neuroleptic,

Abbreviations: haloperidol (HAL), N-methyl-D-aspartate (PTZ), phencyclidine (PCP).

phencyclidine.

(NMDA), pentylenetetrazol

Introduction Similar to many abused stimulants (PCP) has dopamine

agonist

(e.g., cocaine and amphetamine),

properties.

PCP does not bind

699

phencyclidine

directly

to dopamine

$29.00

700

J. L. Wiley

receptors; uptake

rather,

(Johnson

interaction

it acts indirectly

and Snell,

with

a receptor

et. al., 1989).

(Rothman

1986).

site associated

In addition,

channel of the N-methyl-D-aspartate of

PCP's

mediated

behavioral

by increasing

effects,

with

the reuptake

PCP binds its

blockade

release

properties

and slowing re-

may be produced carrier

to a noncompetitive

(NMDA) receptor complex

including

via its noncompetitive

dopamine

PCP's dopaminergic

site within

(Lodge et al., 1989).

discriminative

stimulus

of the NMDA receptor

by

for dopamine the Many

effects,

(Balster

are

and Willetts,

1988). Although

PCP has no known

antagonist

suggest

that acute doses of dopamine

effects

of PCP.

weaving,

and

Dopamine

locomotor

antagonists

activation

noncompetitive

NMDA antagonists

et al., 1991;

Sturgeon

doses of haloperidol to discriminate In human;,

Although

effects

that drug discriminationmay interaction

between

the

therapeutic

The

purpose

Since adapted

to from

stimulus

benefits

a

drug's

common

effects

method

discrimination

training

administration,

tolerance

fading

of the effective

In other words, Researchers Young, 1993),

and to

a drug

used

training

avoid

administration

effects and offer

studies that have examined

are most

apparent

with

the effects

of

during

performed

period

stimulus

(for a review,

to discriminate

and

to

repeated

in studies

the

of

see Young

during

confounding

of

was performed

1986)

supplemental drug

and

that, when drug

be masked

and Sannerud, weaker

stimulus

most

stimulus.

effects

of drugs

under conditions

and

(Wiley et al., pronounced

administration. learning

by

1989).

et al., 1988; Sannerud is

of was

discriminative

may

a progressively

(Emmett-Oglesby

study

supplemental

effects

to the discriminative

Emmett-Oglesby,

is suspended

of haloperidol

the

of repeated

in the present

tolerance

the

discriminative dose

often

employed

(Gaul et al., 1989), A'-tetrahydrocannabinol

possible

model

animal

it is possible

of this type of study have shown

such as morphine

(Wood

training

with dopamine

is an

1990); hence,

to examine

is most

in studies

continued

the rats may learn

cocaine

was

the procedure

to the

of classes

study

The results is

1987), amphetamine

discrimination order

of

have found that tolerance

from a variety

treated

resemble via PCP's

have employed acute dosing paradigms;

of neuroleptics

effects,

of drugs.

Most previous

1986).

on PCP discrimination,

administration

the

(Balster,

antagonists

of the present

of haloperidol

repeated

is often

Drug discrimination

acute

in rats trained

is mediated

provide a model of PCP's psychotomimetic

PCP and dopamine

dosing.

administration

PCP psychosis

in humans

1992; Sagratella

effects which

PCP psychosis

head-

PCP-like

In addition,

1988; Browne,

psychotomimetic

et al., 1984).

of these effects.

however,

stereotypy,

of the PCP stimulus

whether

of evidence

of PCP and other 1992).

and Balster,

to produce

effects,

lines

some of the behavioral

decrease

doses

and Kulkarni,

(Beardsley

of drugs

several

and Adams, 1981; Hoffman,

attenuation

it is unclear

or glutamatergic

clues to the mechanism

tolerance

partial

(Fox, 1979; Giannini

of the subjective

by high

(Castellani

PCP has the potential

dopaminergic antagonists

produce

site,

may attenuate

such as haloperidol

induced

et al., 1981; Verma

PCP from vehicle

schizophrenia.

at its NMDA

antagonists

effects,

of suspended

when

Thus,

in

repeated training.

Method

Fourteen

experimentally

naive male Sprague-Dawley

rats were maintained

at 85% free-

701

RepeatedhaloperidolandPCPdiscrimination feeding

body

weights

individually training

and testing

of 20-22Y

by

of

colony

and were

room

Rats were housed chow ration. transported to the laboratory for

daily

The animal colony room was maintained

sessions.

with a 12-hour

to water

restriction

in an animal

light-dark

cycle (lights on at 7 a.m.).

at a temperature

Rats had free access

in their home cages.

Drugs

PCP HCl

(National

Dosages

saline.

PA) was

House, solution

Institute

on Drug

prepared

containing

by

adding

1.8 mg methyl

Rockville,

Abuse,

Haloperidol

of PCP refer to the salt.

MD) was

to commercially

saline

paraben,

dissolved

in 0.9%

(McNeil Pharmaceutical, available

0.2 mg propylparaben,

Spring

5 mg/ml

stock

and lactic acid.

ADDSratUS

Six standard cubicles.

operant

A pellet

to a food cup located chamber. watt

delivered

between

Fan motors provided located

houselight,

testing

sessions.

Fairfield,

VT)

contingencies

(BRS/LVE, Laurel, MD) were housed

chambers

dispenser

two response

above

the

and

MED-PC

food

cup,

with

software

levers

mounted

and masking

ventilation

A microcomputer

in sound-attenuated

45-mg BIO SERV (Frenchtown,

was

Logic

NJ) food pellets

on the front wall

noise for each chamber. illuminated

during

'1' interface was

training

and

(MED Associates,

used

East

to control

schedule

for training rats in the two-lever drug discrimination

paradigm

and to record

(MED Associates)

of the

A seven-

data.

Procedure The initial procedure

used in this study was similar 1992). press

Rats were another

schedule

of

Following

food

received chambers weekly.

three

15 days 1

training,

major

goals

provides

an

was

with PCP (2 mg/kg)

injected

10 min

rats

and to

30 (FR-30) pre-session.

were

trained

on a

was to train the rats to switch levers when

this procedure,

10 min

of the

later.

An equal number consecutive whereas

(Balster et al.,

to a fixed-ratio

(38 sessions),

rats

first

(i.e., saline-saline

twenty

sequence),

This

phase

on

on the

an injection min

the

later,

in the operant

of the experiment trials

correct

incorrect

of

they

PCP (i.e., saline-PCP

and were placed

of PCP and saline

responses

responses

received

trial;

lever

lever

lasted

was conducted resulted

reset

in

the ratio

lever. of

the

on the cumulative

of haloperidol

saline

studies

two 5-min training or test (control) trials per

start

study

on PCP discrimination,

discrimination

or

injected

according

(i.e., PCP-PCP sequence)

trial

on the correct

administration Table

second

three weeks.

During

haloperidol of

the

of saline

of a reinforcer

requirement The

10 min before

the

approximately delivery

During

or a sham injection for

PCP

discrimination

changed.

an injection

sequence),

saline

of the trials procedure

conditions or PCP

of the

one lever when with

in which they received

The purpose

saline

injected

reinforcement.

acquisition

stimulus

to press

lever when

trials procedure day.

trained

to the method used in previous

to

(1)

assess

the

the effects

acute

effects

of

of 14 days of vehicle

PCP dose-effect

administration

outline

were

(2) to assess

of

training was suspended

the

on

curve, and (3) to assess the effects the cumulative PCP dose-effect curve.

training

and

testing

for two 2-week periods.

protocol. Briefly, During these times, rats

702

J. L. Wiley

were

injected

once

(second period). before

and

included

daily with

vehicle

A cumulative

after

each

6 consecutive

repeated 5-min

(first period)

dose-effect dosing

trials.

or with

curve determination regimen.

The

Ten min before

0.5 mg/kg

haloperidol

with PCP was conducted

cumulative the first

dosing

trial,

procedure

each rat was

injected with saline and was placed

in its home cage until the start of the trial.

Ten

min before

each

rats

the

cumulative

dose of PCP was equal to 0.3, 1.0, 2.0, 3.0, and 10.0 for each successive

subsequent

trial,

trial.

Inter-injection

training

dose of PCP were conducted

The procedure cumulative test

responses

for control

dosing

phases

on both

also

study,

tested

with

PCP, prior

The procedure

2-trial sequence 5-min

saline

substitution

tests

with

to ensure continued and PCP was

that rats received and

dose-effect

acute

doses

such

antagonism

identical trials

that

saline

and

the

stimulus control. to that of the

only two trials. lasted

and

PCP

interval

curve determinations

of

saline

and

During 5 min

and control

haloperidol,

to and at the end of the repeated

dosing

all with

alone

tests, and

in

regimen

with

was comprised

of a

(0.1 or 0.3 mg/kg) was injected 45 minbefore

the

for testing acute doses of haloperidol

in which haloperidol

trial

(Inter-injection

with

Control

of PCP

levers reinforced.

with

haloperidol.

an injection

20 min.

periodically

except

to the cumulative

were

combination

first

the

was

trials

procedure,

of

In addition rats

interval

received

(2 mg/kg)

was

injected

10 min

before

the second

trial.

was 60 min.) Table 1

Training

and Testing Protocol for Effects of Repeated

Acquisition training (38 sessions)

_____>

_____>

Trials training

----->

Suspended _____> training with daily veh injections (14 days)

Pre-HAL cumulative PCP curve

------>

Post-HAL substitution and antagonism tests (15th day)

Haloperidol

on PCP Discrimination

Control tests with PCP and saline

Post-Veh cumulative PCP curve

____->

----->

Discrimination Pre-HAL -----> control training tests with (6 days) PCP and saline

Pre-HAL acute substitution Suspended ------> training with and antagonism tests daily injections of HAL 0.5 mg/kg (14 days)

______>

Postl-HAL cumulative PCP curve (16th day)

Pre-Veh cumulative PCP curve

Continued ------> suspended training (5 days)

>

Post2-HAL ------> cumulative PCP curve

Data Analysis For each test session, mean percentage

of PCP lever responding

and mean response rate

703

Repeated haloperidol and PCP discrimination

were calculated.

(responses/set) that had

less

than 0.05

Full substitution

group means.

ED5,,'s (with 95% confidence linear lever

Data on percentage

responses/set

regression responding

dose-effect

was defined

NC).

as greater

limits) were calculated

plotted

against

whether

curves following factorial

measures

during substitution

from the

for percentage

of the dose

dosing with vehicle

(Goldstein,

between

of

of PCP1964).

the pre- and post-

or haloperidol,

separate 2X5

(ANOVA) with time (pre vs. post) and PCP

of variance

was used to perform

of PCP-lever

each ANOVA

ANOVA was used to analyze

and antagonism

for rats

excluded

the least squares method curve

on group means for percentage

linear models procedure

A 2X4 repeated

log,, transformation

repeated

analyses

responding

were

than 80% PCP-leverresponding.

using

or not there were differences

dose (O-3 mg/kg) were conducted A general

of PCP-lever

a test session

on the linear part of the dose-effect

In order to determine within-subject

during

responding.

(SAS Institute,

differences

tests with acute doses of haloperidol.

hoc tests

(a - 0.05) were used to specify differences

(Brunning

and Kintz,

revealed

Cary,

in response

rates

Duncan DOSE

by significant

ANOVA's

1977).

Results Effects

of Acute

Figure

1 shows

haloperidol mg/kg)

Doses

the effects with

of substitution

after repeated given saline,

dose

substitution

(2 mg/kg)

and antagonism

of PCP.

tests.

the PCP stimulus

before

Haloperidol

did not

Effects Figure

suspended

with

(0.3 mg/kg)

performed

of control

tests with

responding

when

injection

produced

with

PCP

in any

partial

Although

attenuation

decreased

responding

than 0.05 responses/set.

decreased

response

of the

this attenuation

was severely

of PCP-lever

greater

dose-dependently

from

rates

across

of was

in most

represents Compared all tests

~<0.05].

of Repeated 2 shows

responding

Results

test.

test, responding

this test and the mean percentage

haloperidol

[E(3,39)=23.4,

haloperidol.

generalize

The 0.3 mg/kg dose of haloperidol

in the pre-haloperidolantagonism

and

dosing

on the PCP lever following

data from the only two rats that responded to vehicle,

(2 mg/kg),

(0.1 and 0.3

repeated

are also shown.

PCP

haloperidol

tests with haloperidol

predominantly

in the post-haloperidol

during

saline,

tests with

that, while rats showed low levels of PCP-lever

they responded

training

not evident

PCP

tests with

and antagonism

dosing with haloperidol

saline and PCP reveal

animals

of substitution

(0.1 and 0.3 mg/kg)

in combination

Results

the

of Haloueridol

Dosing with Saline

the effects

(top panel) training

curve for percentage

of cumulative

and response

and daily

rate

doses

of PCP on percentage

(bottom panel)

dosing with vehicle.

of PCP-lever

responding

before

of PCP-lever

and after

The post-vehicle

14 days of

PCP dose-effect

showed little change from the pre-vehicle

curve

(pre ED,, - 0.6 mg/kg, CI-0.4-1.0 vs. post ED,, = 0.4 mg/kg, CI-0.1-1.5). ANOVA on mean percentage of PCP-lever responding did not reveal any significant main effects for time [F(l,13)-2.9, As

expected,

observed across

~>0.05]

a significant

[E(4,52)-28.1,

all doses.

nor any significant

dose-dependent

Q-O.OOl].

Response

interaction

increase

[F(4,52)==1.3, ~>0.05].

in percentage

rates between

of PCP-lever

was

the two curves were similar

704

J. L. Wiley

r-

T

1

\,*::,* .,-,\,:\ :;:;:;:;: y;:;:;: ~,-:,-,~ :;:;:;:;: ~:,~,.,* ~,~,~,.,. :;:;:;:;: y;:;:;: :;:;::::: *:,::. y;:;:;: ~,~,‘,~,’ :;:;:;:;: .,:‘,:.

~ SAL

:*,\,:‘ ..\..

PCP

HAL.1

HAL .l +pcp

PM-HAL

&ll_ HAL.3

HAL. .3 +PCi J

HAL .3

,

HAL.3 +PCP,

POST-HAL

0.0 SAL

PCP

HAL.1

HAL.1 +pcp

HAL.3

HAL.3

HAL.3

+PCp,

PRE-HAL

HAL.3 +KP ,

POST-HAL TEST CONOrTION

Fig. 1. The effects of substitution tests with saline, PCP ('2rag/kg), and HAL (0.1 and 0.3 mg/kg) and antagonism tests with HAL (0.1 and 0.3 mg/kg) + PCP (2 mg/kg) before Results of substitution and antagonism tests with repeated dosing with haloperidol. HAL (0.3 mg/kg) performed after repeated dosing with haloperidol are also shown. Values represent means (+ SEM) for percentage of PCP-lever responding (n-11-14; except n-8 for substitution and antagonism tests with 0.3 mg/kg haloperidol before repeated dosing and n=2 for these tests after repeated dosing) and response rate (n=14). Effects

of Reseated

Figure

3 shows

responding suspended

training

continued

dosing

suspended

compared

doses

of PCP on percentage

with

training).

six days after the first post-haloperidol Repeated administration of haloperidol

the ED,, for percentage to the pre-haloperidol

The ED,, for the second post-haloperidol

~<0.05]

Post hoc analysis

and a significant

of the interaction

2.0, and 3.0 mg/kg) increased haloperidol

dose-effect

and after two weeks of The second posthaloperidol.

0.5 mg/kg

time

showed

percentage

curves compared

of PCP-lever responding was 1.4 ED,, of 0.7 mg/kg (CI-0.6-0.9).

curve was between

mg/kg, CI-0.5-1.5), providing evidence of recovery ANOVA on percentage of PCP-lever responding revealed [F(4,46)=18.6,

of PCP-lever

rate (bottom panel) before

curve was determined

PCP discrimination;

(CI-0.7-2.9),

of cumulative

and response

and daily

dose-effect

(with

attenuated mg/kg

the effects

(top panel)

haloperidol curve

Dosinv with Halooeridol

these two values

from the effects a significant

(ED,, = 0.9

of haloperidol.

main effect for dose

X dose interaction [r(8,56)=2.6, D
of Pep-lever

responding

to the corresponding

in the pre- and post2-

vehicle

tests, percentage

RepeatedhaloperidolandPCPdiscriminatton

of PCP-lever repeated only

responding

during the cumulative

dosing withhaloperidol

at higher

responding

doses

following

(2.0

and

administration

following increased

percentage

of PCP-lever

of the 1 and 3 mg/kg doses of PCP was significantly

during the postl-haloperidol

PCP-lever

during

the pre-haloperidol

curve immediately

curve) was significantly

In addition,

3.0 mg/kg).

decreased

three dose-effect

dose-effect

(postl-haloperidol

705

dose-effect curve.

curve compared

Response

to responding

rates were similar

on the

across

all

curves.

100

“0

7

SAL

PCP

b

i

d.3 CUMULATIVE

0.01-7 SAL

PCP

b

;

;

lb

DOSE (mg/kg)

0:3

lb CUMULATIVE

WSE

(mg/kg)

Fig. 2. The effects of cumulative doses of PCP on %PCP-lever responding (top panel) and response rate (bottom panel) before and after 14 days of suspended training and daily dosing with vehicle. Values represent means (2 SF.M) of data for lo-14 rats. Single data points near the Y-axis are results of control tests conducted with saline and PCP prior to the pre-veh dose-effect curve. Discussion Acute

Haloneridol

Similar

and Partial

to previous

studies

Attenuation (Beardsley

of PCP's Stimulus and Balster,

study showed that acute dosing with haloperidol of PCP's discriminative

stimulus properties,

responding

(73.4 %PCP-lever

was partial

Effects

1988; Browne, 1986), the present

produced

a dose-dependent

attenuation

This reduction in percentage of PCP-lever responding), and was accompanied by response

706

J. L. Wiley

rate by

Generally,

decreases.

discriminative the way

(Shannon resemble

stimulus

that

naloxone

et al., that

discriminative

a

days

of repeated severely

antagonist

the discriminative

blocks hence,

haloperidol's

competitive

stimulus

were

either lever.

1984);

of

a competitive

will

completely

effects of a drug acting at the same receptor,

dosing

with haloperidol in most

acute

attenuation

was no longer evident

(0.5 mg/kg/day);

rats during

effects

however,

this test and many

In fact, all but two rats failed to meet response

2 0.05 responses/set)

for inclusion

in calculation

the

of morphine

on PCP discrimination

The

antagonist.

effects by haloperidol

decreased

stimulus

effect

block

as exemplified did not of

PCP's

1 day after 14 response

rates

did not respond rate criteria

of the mean for percentage

on

(i.e., of PCP-

lever responding.

SAL

0.0 J

-

PCP

1

0.3

2

CUMULATNE

DOSE @q/kg)

0.3

1

3

10

--a SAL

KP

0

CUMULATIVE

2

3

10

DOSE @g/kg)

Fig. 3. The effects of cumulative doses of PCP on %PCP-lever responding (top panel) and response rate (bottom panel) before and after two weeks of suspended training and The second post-ha1 dose-effect curve was daily dosing with 0.5 mg/kg haloperidol. determined six days after the first post-ha1 curve (with continued suspended training). Values represent means (& SEM) of data for 9-14 rats (except means for percentage of PCP-lever responding at the following points: n=8, 3 mg/kg, postl-hal; Single n=l, 10 mg/kg, postl-hal; n=3, 3 rag/kg, postZ-hal; n=l, 10 mg/kg, postZ-hal). data points near the Y-axis are results of control tests conducted with saline and PCP prior to the pre-ha1 dose-effect curve.

707

RepeatedhaloperidolandPCPdiscrimination Interestingly,

rats were more sensitive

0.3 rag/kg of haloperidol A similar

tests.

sensitization

1993) and response following its

repeated

dosing

effects

Tarsy

and Baldessarini,

studies

binding

suppose

contribute

Reseated

these

Haloueridol

contrast,

on

days disrupted respond

curve

improvement. haloperidol

control

lever

this procedure. decrease

in

following decrease maximum

Decreases

the

maximum

an acute

efficacy

adverse

rates.

response

without

effects.

(0.5 mg/kg)

producing

in the first post-

curve;

in the maximum

thus,

efficacy

discriminative

PCP-lever

responding

repeated of PCP in

stimulus

were overlapping. also

in combination In contrast,

a

observed

with PCP, this the decrease

in

not associated

These results suggest that repeated on PCP discrimination

effects

Although was

repeated dosing with haloperidolwas effects

in the

showed some

achieved during the

post-haloperidol

intervals

changes

control

to 69.3%

rate suppression.

different

In

for 15

responding

compared

a 30% decrease

of

for two weeks had rate

half of the rats (i.e., they did not

of PCP-lever

99.6%,

that differences

the repeated

between

may be related dosing

training

regimen,

of stimulus

of the extended since

the effects

administration than does acute

control.

period

the half-life

of repeated

to the extended this explanation

during repeated

and the pre- and post-vehicle

Alternatively,

its

of 0.3 mg/kg haloperidol

of haloperidol

disruption

effect

in these

the number of

at least in some rats.

the fact that suspended a similar

on

PCP),

95% confidence

of PCP following

it is possible

haloperidol

1981;

effects of dopaminergic

dosing with haloperidol

second

by response

may produce

during

employed

increased

dosing with vehicle

or

in the ED,, 's for PCP's

injection

in response

administration

regimen

Six days later, stimulus

percentage

of haloperidol administration,

in the

although

was accompanied

training

PCP

receiving

rates.

produced

with decreases

While

by

curve was

88.9%

with haloperidol

also were observed,

dosing

to the behavioral

in approximately

after

dose-effect and

has

to that which

and repeated

and repeated

for response

curve

dosing with neuroleptics

(Burt et al., 1977). Thus, it is reasonable in dopamine-innervated brain areas may

The maximum mean percentage

pre-haloperidol

the

changes

control

training

stimulus

in

to

PCP Discrimination

training

stimulus

on the drug

dose-effect

dosing

Disruuts

suspended

haloperidol

sensitivity

dosing with neuroleptics.

suspended

effect

and Porter,

1983; Burt et al., 1977; Schechter,

supersensitivity

repeated

increased

after chronic

The haloperidol

receptor

(Villanueva

that resembles

An

study is comparable

to the observed

As expected, little

agonists

sites in the striatum

that

drugs following

a neuroleptic 1985).

and Steranka,

1974).

and in the present

dopamine to

(Barrett

rate-decreasing

effects of

than during acute

(Wiley et al., 1994) effects has been observed

(Janssen,

of dopamine

also been reported

decreasing

dosing with haloperidol

to response

of pimozide,

actions

to the response-rate

repeated

duration-increasing

neurochemical

behavioral

following

period

does not account

dosing with vehicle

In addition, PCP dose-effect

of suspended

versus acute of suspended

similarities curves

for

did not produce among the pre-

argues against

any

training.

for elimination

of haloperidol

from the brain

is at least one week responding

(Cohen et al., 1992), residual haloperidol could have disrupted during the postl-haloperidol PCP dose-effect curve determination; however,

this explanation haloperidol

on

does not account PCP's

for the selective

discriminative

stimulus

effect

effects

of repeated

versus

its

dosing with

response

rate

708

J. L. Wiley

effects. effect

Response

rates

ware

similar

across

pre-

and post-haloperidol

PCP dose-

curves.

Similarly, repeated

the

disruption

dosing

tolerance.

with

of

tolerance

First,

PCP's

haloperidol

shift of the dose-effect

haloperidol

curve to the right.

were

the result

on stimulus

control

are more accurately

data which suggests

curve.

that repeated

drug,

characterized

This observation

cross-

by a parallel inspection in the

before and after chronic

of individual

doses

Haloperidol's

as a disruption is consistent

for the PCP binding

of

that differences

curve.

dosing with haloperidol

(+)SKF 10,047,

following

type

study, visual

responding

in the effects

a

indicated

reveals

shift in the entire dose-effect

shift of the PCP dose-effect of the PCP-like

curves

effects

represent

is typically

of PCP-lever

of changes

stimulus

not

In the present

dose-effect

curve for percentage

rather than a parallel

does

to a drug effect

of the pre- and post-haloperidol PCP dose-effect

discriminative

probably

of PCP effects

rather than a

with biochemical

does not alter the affinity site (Itzhak and Alerhand,

1989). Possible The

Halooeridol

disruption

curves

Withdrawal

of stimulus

may have

resulted

drug

Bronson

pentylenetetrazol following

results

of clinical

effects

following

produces (PTZ)

5 days

anxiogenic

from vehicle

chronic

dosing

conceivedly

during

another

study PTZ (10 mg/kg)

1990; Gardos

1992, 1993; Wiley

to PCP's discriminative

from haloperidol

the postl-haloperidol

on the

PTZ

did not antagonize

when

given

In addition,

the

withdrawal

et al., 1978; Lacoursiere

anxiolytic

stimulus effects,

PCP dose-effect

for

the anxiogenic

may produce

et al., 1992).

could have

Withdrawal

lever

haloperidol.

shown to have potential

and Balster,

control

to discriminate

that neuroleptics

(Dilsaver,

dose-effect

in both animals and humans;

responded with

PCP

from haloperidol.

effects

dosing

studies have suggested

effects contribute

of PCP (Browne,

the post-haloperidol

of withdrawal

of repeated

PCP has been

al., 1989; Wiley withdrawal

during

(1993) found that some rats trained

vehicle

et al., 1976).

control

from effects

from chronic haloperidol example,

Effects

effects

(Porter et

If these anxiolytic

an anxiogenic

negatively curve.

effect of

influenced

stimulus

On the other hand,

the discriminative

stimulus

in

effects

1986).

Conclusions The

effects

properties middle

doses

haloperidol curve. when

of repeated of

PCP

in some

PCP dose-effect

Unlike

given

the decrease

in combination

effects

of repeated

effects

are

emphasize

dosing

with

of PCP may be characterized

not

curve

rather

than

compared

of stimulus

as a parallel

shift

to the pre-haloperidol

PCP dose-effect

of haloperidol,

with

injection

of haloperidol suppression

research

chronically

of

on PCP's response

into the effects in humans.

at the

in the post-

with

an acute

stimulus

control

in the discrimination

for further

drugs that are administered

on the discriminative

as a disruption

in PCP's maximum efficacy

administration

associated

the need

rats

haloperidol

procedure

the disruptive

discriminative

stimulus

rates.

findings

These

of repeated

dosing

with

709

Repeatcdhalaperidoland PCP discrimination Acknowledgements The author his National fellow

gratefully

acknowledges

Institute

on Drug Abuse

supported

by NIDA training

the support provided by Dr. Robert Balster and The author is a postdoctoral Grant DA-01442.

grant DA-07027.

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Inquiries

and reprint

requests

should be addressed

Dr. Jenny L. Wiley Department of Pharmacology & Toxicology Medical College of Virginia MCV Station, Box 980613 Richmond, VA 23298-0613, U.S.A. Phone: (804) 828-2067 FAX: (804) 828-2117

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