ofP/mnnoco/ogy,202 ( I991 ) 19 I - 199 8 1991 Elsevier Science Publishers B.V. All rights resrlved l;n14-1Y99/91/%1)3.5() ADONIS 001429999lO1)SXhG

Europcmr bond

1Yl

EJP 5201X

Role of dspamine D, and D, receptors in mediating the d-amp discriminative cue

Received IS April 1991. accepted 25 June 19‘11

The role of D, and D, dopaminc (DA) receptors in mediating the discriminative cue produced by d-amphetamine (0.3 mg/kg) in rats has been assessedby using compounds which cxcrt strong selectivity for each of these DA receptor subtypes. The D, agonists quinpirolc and RU 24213 substituted complctcly for d-amphetamine, while the D, agonists SKF 35393 and SKF 81297 failed to exert such effects. On the other hand, the D, antagonists raclopridc and YM 09151-2, and D, antagonists SCH 23390 and SKF 83566, all complctcly blocked d-amphetamine discrimination. The D, antagonists produced more pronounced inhibitory effects on response rate than did D, antagonists. Quinpirole substitution for d-amphctaminc was blocked by YM 09151-2, but not by SCH 23390, while the locomotor stimulatory cffcct of quinpirolc was inhibited by both drugs. The present findings confirm that D, receptors play a primary role in the d-amphetamine discriminative cut. while the precise role of D, receptors remains to be disclosed, d-Amphetamine discriminative cut; Dopaminc D, rcccptors; Dopaminc D, rcccptors: Rcccptor interactions: Dopaminc rcccptor agonists; Dopaminc rcccptor antagonists

1. Introduction

Compounds which selectively interact with D, or D2 dopamine (DA) receptors have provided important information concerning the functional role of thcsc distinct recognition sites (see Clark and White, 1987; Waddington and O’Boyle, 1989 for reviews). Evidcncc suggests that D, and D2 receptors can interact in either a synergistic or in an opposing fashion. Of particular interest is the suggestion that a critical level of D, receptor stimulation is required for the exprcssion of certain functional effects mediated by D, receptor stimulation. Behavioural work has provided three main pieces of evidence for this hypothesis. Firstly, selective Dz receptor agonists cannot reverse the akinesia produced by the monoamine-depleting agent reserpine unless D, receptors arc concurrently stimulated by D, receptor agonists (Gcrshanik et al.. 1983; Jackson and Hashizume, 1986; White ct al., 19%). Secondly, the locomotor stimulatory effects of D, agonists are inhibited by selective D, antagonists (Mailman et al., 1984; Pugh et al., 1985). Finally, the

Corrcspondcnccto: D. Cl;& Dep;uImrnl of Psyrh0logy.Uni\‘crbilq iiF Ru;lding. Earley G;II~. Whitcknighls. Rs;lJillg. RGO XL. U.K. .itzl. 44.73J.3lX 5X.

full spectrum of stereotypies produced by mixed D,/DZ agonists (e.g. apomorphinc and d-amphetamine) is not observed with selective D, agonists unless they are administered with D, agonists (Barone et al., 1986; Arnt et al.. 1987, 1988). A synergistic interaction between D, and D, receptors has also been observed in clectrophysiological studies (Carlson et al.. 1987: White. 1987: Wachtel et al., 1987). Nielsen and colleagues (1989) have recently provided evidence that D, and D, receptors are both involved in the discriminative cue produced by the indirect DA agonist d-amphctaminc. Antagonists selcctivc for tither D, or D, receptors blocked the cueing properties of d-amphetamine (see also Nielsen and Jepscn, 1985). On the other hand, selective Dt agonists substituted for the stimulant while a variety of sclcctivc D, agonists did not generalist. Interestingly, the D, antagonist SCH 23390 did not inhibit pcrgolide substitution for the d-amphetamine cue despite blxking the motor activating cffccts of this D, agonist 1’1 a different

group of rats. On the basis of these findings.

Nielsen et al. (1989) concluded that D2 receptors play a primary role in the d-amphetamine discriminative cut. In addition, these investigators suggested that D, and Dz rcccptors in the dopaminergic system mediating d-amphetamine discrimination arc less tightly COUpled than those in dopamincrgic motor systems.

\\‘Ch:t\C Char;tctCriwd the role of D, and D,

rcccp-

tars in j-;,,,lpl~et~rrnilIc (0.5 mp/kp) cliscriminnticlr~ h!, &tern~ining the ahilit> of sclectivc agonists tct suhstitutu for. and x+xtivc

antsgonists

to inhibit.

puter which was programmed photocell

interruptions

in ONLIBASIC

to record

of greater

than 0.5 s duration.

procedures

have been detailed

the WC. In

;dJition.

\vc have csamincci the ability of SCH Il.?~~J,O ;md the >clcctiw D, antagonist YM 01J15l-1 to inhibit

quinpirok locmmtor

suhstitukm stimulatory

for d-arnphetaminc. and the et’fccth of the DZ agonist. The

latter cspcrimcnt W;IS carried out in tk drug discrimination rats. to rule out the possibility that the difftzrtmtial r‘ffcct of SCH 2.3290 obscned hy Niclscn and

The

discrimination

elsewhere for :I study using the same population of rats (Exncr ct al.. 10X9). Initially. rats were randomly assigned to one of the four operant

boxes. For each box,

half of the animals were randomly

assigned to the right

collt2apucs( l9S9) in thcsc paradigms was not rclatcil in

Icvcr as the drug-appropriate

s0mC Way 1:) the long-tCrm rCpCiltCd itdn~inistrati0n Of d-ilIl~ph~tiul~inC. Parts of this work ha\V been rcportcd

to the left lever. This arrangement.

and the fact that

saline

each other

in abstract form clscw4icrc (Furmidgc

et al.. IW%i. h).

and

drug

pseudorandom

lever and the other half

sessions followed

in a

order, served to control for the devel-

opment of position cues based on olfactory stimuli by animals that were run in the same box (Extance and 2. Materials

I9ti I ),

Goudic.

and methods

Throughout the study, rats were injected i.p. with either 0.S mg/kg d-amphetamine sulphate (the train-

2.1. .-trritturl.s

ing drug). or 0.9% Fifty six male. Sprague-Dawlcy 0k1c Ltd..

BiCCstCr. U.K.)

albino

in the operant

rats (Harlan

were fwd-dCprivcd

to ap-

prosimatcly STci of their free feeding weights (initial weight 30-300 g) by restricting food intake to ilIl awagc of 20 g rat chow per day. Water was freely available. The rats wcrc housed in pairs in a room maintained at ;I constant tcmperaturc (?I-23°C). Lights were on from 07:OO to 19:OO h.

saline,

15 min before being placed

boxes. Injection

phase of training. Animals were injected with saline and trained to press the saline-appropriate lever for food pellets. Following

reliable

Saiine and d-amphetamine

under the

sessions were then carried basis with the restriction

that neither condition occurred in a row. The rats were trained drug discrimination cspcrimcnts wcrc conin four identical. commcrciiilly milnUfaCtUrCd

performance

saline condition, they learnt to respond on the drug-appn~~priate lever following d-amphetamine injections. out each day on a random

The ducted

volumes were 1 ml/kg.

Only the correct lever was present during the initial

ratio (FR)

more than three days to respond on a fixed

20 schedule on each lever using an ascend-

ing FR schedule independently for each condition. Discrimination training was initiated once the rats

operant bosCs (Camp&n Instumcnts Ltd., U.K.). each measuring 20 cm high with ;I 3 X 23 cm grid floor.

were responding

Each box contained two retractable levers mounted on one wail. with a food hopper positioned equidistant

ing these training sessions of 25 min duration, both lcvzrs were available. but only responses on the appro-

between the lcvcrs. Food pellets were delivcrcd hy automatic dispcnscrs. The boxes wcrc dimly lit by a

priatc

centrally

positioned

2.X W light and were enclosed

in

light- and sound-attenuating chambers. Fans provided ventilation and masking noise. Equipment was controlled.

and data collected.

by an Acorn

Atom

micro-

computer (Acorn Computers Ltd., Cambridge, U.K.) using programs written in ONLIBASIC (Paul Fray Ltd.. Cambridge, U.K.) The activity expcrimcnt was conducted in four idcntiCill clear Pcrspcx boxes measuring 3.5 X 35 X 30 cm and containing a metal grid floor ( 1 cm’ mesh). Screens were placed bctwccn the individual hoxcs to prcvcnt visuai distraction. Locomotor activity was measured by means of two infra-red photocells and associated dctectors. The photocells wcrc positioned on the sides of the box. 1X cm apart and S.S cm above the floor. l’hc dctcctors were linked to an Acorn Atom microcom-

lcvcr wcrc

Incorrect grammed

reliably on the FR20

rcinforccd

schedule.

on an FR20

Dur-

schedule.

responses were recorded but had no proconsequences. The time in seconds to com-

plctc the first 20 responses on the correct lever (latency) and the percentage of drug lever responses prior to delivery of the first food pellet (100 x no. of drug lever rcsponscs

divided

by no. of drug + saline

sponses) were recorded. dcrivcd

by calculating

lever

re-

A response rate measure was the number

of responses

per

minute bcforc dclivcry of the first reinforcer (60 x no. rcsponscs before food pellet delivery divided by latency). Discrimination

training continued

until rats reached

criterion pcrformiincc (nine out of ten consecutive sessions with more than 8Or/( correct lever presses bcforc

the

animal

was then randomly

first

reinforccmcnt

was delivcrcd).

Each

assigned to a subgroup of

rats (N = X. if not stated otherwise)

for testing with a

1513

specific drug or drug combination. No reinforcement was given during test sessions; the rat was removed from the operant box on completion of twenty responses on either of the levers. The number of drugand saline-appropriate lever responses, and the latency to complete twenty responses on either of the levers were recorded. Each latency value was converted to a response rate measure. Animals were randomly selected to participate in a series of generalisation and antagonism studies with compounds selective for either D, or D2 receptors. They were injected with different doses of drug in a random order to determine whether these compounds substitute for d-amphetamine or block the cueing properties of this stimulant. The effects of different DA antagonists on quinpirole substitution for damphetamine was also examined. Animals received quinpirole (250 pg/kg) eithft alone, or in combination with SCH 23390 (50 pg/kg) or YM 09151-2 (50 pg/kg). Each rat received these drug conditions in a random order. If any animal failed to produce a minimum of 80% d-amphetamine-appropriate responses in the quinpirole control session, it was excluded from the study and another animal was used. Eight of thirteen rats reached this criterion and were included in the analyses. Test sessions were separated by at least one damphetamine and one saline baseline session which provided control data. If discrimination performance deteriorated between test sessions. further training was carried out until performance restabilised. if under any condition an animal failed to respond with at least ten lever presses in a session, the data were considcrcd unreliable and excluded from analysis. Similarly, data were not analysed if less than half of the rats tested under a condition failed to respond with at least IO presses.

The ability of YM 09151-2 (SO pg/kg) and SCH 23390 (50 pg/kg) to inhibit the locomotor hypcractivity produced by quinpirolc was assessed. A group of the discrimination rats described above wcrc used. These rats were maintained on a pseudo-random 0.S mg/kg d-amphctaminc/salinc regime, cxccpt on days where activity testing took pl,ace. Animals were habituated to the pcrspcs photocell boxes for a period of 60 min. They were then injected with the relevant drugs, and locomotor activity was monitored for I h. Locomotion counts wcrc rccordcd when the photocell beams were intcrruptcd in strict scqucncc, i.e. the rat moved through the front hcam and then the rear beam, or vice versa.

2.5. Statistical analyses

For each drug discrimination study. saline and damphetamine control values were obtained by averaging the control data for each of the relevant baseline sessions which preceded drug tests. In order to normalise distributions. drug lever responding percentages were arcsin transformed and response rates were logarithmically transformed. The effects of drugs on these measures were then analysed using the SAS-GLM procedure one-way analysis of variance for a repeated measures design (SAS Institute. Cary. NC, U.S.A.). Provided that this procedure yielded significant overall F values, comparisons between means were carried out using Duncan’s test. Dose-dependent effects on discrimination were analysed using the SAS-PROBIT procedure in order to generate ED,,, and ID,, values. Activity counts were square root transformed [, ( x + 0.5) ] and analysed by a one-way ANOVA.

Unless stated otherwise, the following drugs were administered i.p. in 0.9% saline 30 min prior to testing: d-amphetamine sulphatc (Sigma Chemical Co. Ltd., Poole, U.K.), 15 min prior; quinpirole HCI (Eli Lilly Co., Indianapolis, U.S.A.” 1; raclopride tartrate (Astra. Siidertalje, Sweden*‘). S.C. 60 min prior: RU 23213 (N-n-propyl-n-phcnylethyl-p-(3-hydroxyphenyl)ethylamine) (Roussel, France” 1; SCH 23390 (R-t + j-8chloru-7.3,3,S,-tctrahydro-3-methyl-S-phenyl-1H-3-benzazcpin-‘l-01 malcatc) (Schcring, NW Jcrscy. U.S.A.:” 1: SKF 38393 (2.3.4,5,-tctrahydro-7,X-dihydrohy-l-phcnylIH-3-bcnzazcpinc HCI), in distilled water. and SKF 83.566 (7-bromo-X-hydroxy-3-methyl-I-phcnyl-2.3.4.SHBr) (Smith tctrahydrti-lH-3-benzazepine Kline K: French. Philadelphia. U.S.A.*); SKF 812’17 (2.3.4.S-tctrahydro-O-chloro-7.8-dihydroxy-I-phenylI H-3-bcnzazcbinc HBrI (Lundbcck. Copenhagen, Denmark’“) and YM 09151-2 (NQRS,3RS)-‘i-bcnzyl-2mcthyl-3-p~rrolidinyl-S-chloro-7-mcthoxy-~-mcthylaminobcnzamidc) (Yamanouchi Pharmaceuticals. Tokyo. Japan), in a minimum amount of 0.1 M acetic acid, ncutraliscd with 0.1 M NaOH and brought up to volume with saline. All drugs were injcctcd in a volume of 1 ml/kg cxccpt SKF 38393. which &as injcctcd in a volume of 2 ml/kg.

3. Results

The sclcctive D, agonists quinpirolc and RU 23213 dose dcpcndcntly incrcascd drug lcvcr responding (fig. I), with the highest two doses of each drug producing

SKF

mg/kg

Xl?17

Observation

did

of the

thcsc xssions

not respond (data not shown).

bchiiViWlr

of

the

animals during

failed to reveal any obvious motor dis-

ruption.

The

selective D,

blocked four

All

DA

agonists

rcaponsc rate (fig. 1 and

dose dcpcndcntly

tuhlc

amphctaminc

reduced

While

1). This response disrup-

tion was particularly marked with Three of the animals rrdmirlistcred

the YM

(ID,,, = 4N 091.51-Z

drug-appropriate

the D, agonists. 16.0 rtmg/kg SKF

antagonist

di&iminative

raclopride cut

pg/kg;

complete

d-

reduced

antagonism

in a rcliablc ( > 50%) num-

ber of rats. Only three animals mum requirement

by

fig. 2 and table 1).

also dose dcpcndently

responding,

could not hc demonstrated

_V_VG failed to meet the minimum requirement of I(J lever presses. and the first five animals tested with I!.;!

completely

produced

compieted the mini-

of IO rcsponscs after administration

RU 24213

rlQ(J

0

il

100

75

50

I

I

.016 .031 .063 .125 .250

0.125 0.25

DOSE (mg/kg, i.p.)

0.50

25

0

:

1.0

DOSE (mglkg, i.p.)

SKF 38393 e

100

SKF 81297

100

.

.

I

525 B

P 0 2.0

4.0

0.0

16.0

8 L

0

P 0

L

-

0.25

0;s

DOSE (mg/kg,i.p.)

WSE (mglkg, i.p.)

D: agonia quinpirolc ;rnd KU 371.7. INI! nob the wlective D, agonias SKF 3d.W and SKF X1297. completely d-amphcl;m~ine. Fillcd circles reprcsenl Ihc pcrccnlagc ol drug lever (DL) responses ( + S.E.M.) in I~SI sessions. Empty

Fig. I. Shonh Ihut the xlcciivs wh\tiwte &A\

lor 0.5 mg/kg

( + S.E.M.)

reprwnl

thr numhcr ol’ responses per minute

at different

drug doses. Aslcrixks

indicate

scores Ihat differ signilic;mtly from

(P < W).5). Control perlirrmance ( t S.E.M.) :Or drlc is shtrwn on the Irft. for cl-amplrct;rminc on the right side of the do=reqxjn% curve.rhae are the rnur valucx of all scssion~ immcdi;~tely preceding 1eh1 wsion~. All points rrprescnt the mcan wlueh of eight dine

performance

animals in the D: ugoni~l ~ludics. Six rats par(icipad afwr 3.0 nrg/kg

and tlirec alter

Ih.0 mg/by.

in the SKF 3H.W

Eight rat\ p;rrlicip;lleJ

study. hut only I’ive met 01~ minimum

in IIICSKF XI37

qudy:

WVCII. five

and

rcquiremcnt

ol’ III lever prews

five r;ttx responded

uflor ihu three

of 100 pg/kg, although each of these responded almost entirely on the saline lever (data not shown). The estimated ID5,, value for YM 09151-2 was 14 pg,/kg. Raclopride also produced a marked reduction in response rate and, like YM 09151-2, a significant rate-redlucing effect was observed at a lower dose than that required to attenuate d-amphetamine discrimination. Only four animals responded more than 10 times after the highest dose of raclopride (fig. 2 and table 1). Animals receiving high doses of either D2 antagonist remained still for most of the experimental session and displayed some form of muscular rigidity. SCH 23390 and SKF 83566 also completely antagonised d-amphetamine-appropriate responding (ID5,,s = 13 and 63 pg/kg, respectively; fig 2. and table 1). Notably, SCH 23390 did not reduce response rate

below that observed in d-amphetamine control sessions. Although higher doses of SKF 83566 did inhibit response rate, the effects of this drug were less marked than observed with DI antagonists. Since SKF 38393 is known to be a partial agonist at D, receptors, we considered whether it col;ld reduce the cueing properties of d-amphetamine. The levels of drug lever responding after the combination of damphetamine and 4.0-8.0 mg/kg SKF 38393 were not different to that observed in d-amphetamine control Kessions (d-amp control: 99.2 + O.S%, n = 6; d-amp + 4.0 mg/kg SKF 38393: 77.3 + 19.7%. n = 4; d-amp + 8.0 mg/kg SKF 38393: lOO.W, n = 3). These doses of the partial D, agonist significantly reduced response rate and some rats did not meet the minimum requirement of 10 lever presses (data not shown). Only two of

RACLOPRIDE

100

100

*

I cn

75 I

k! 8 $

50

1

d i

P

% 0

0.2

0.8

0.4 DOSE

P

25 -

G--L.* .006

1.6

.013 DOSE

(mglkg,s.c.)

.013

DOSE

(mg/kg,

E 0

.050

(mglkg,Lp.)

-

L

I

1

.006

.025

2

SKF 83566

SCH 23390

-

-*

25

0.05

0.1

DOSE (mg/kg,

i.p.)

I

1

0.025

.025

0.2

i.p.1

Fig. 7. Illudrutcs the dose-dcpcndcnt inhibition of J-;rn~phcraminc tlisriminu~ion hy the sclcclivu D__ ;Iponihl~ r;~clopridc and \‘hl IN 15 I-Z. and selective D, anlaponisb SCtt LYWI and SKF 3X%)h (N = X per s~uJy). Filld circles rcprewnt ~hc pcrcrntagc of drug Icvcr rcvonscs ( + S.E.M.) after tliffcrcnt doses of DA ;mt;lgonist in combination with 0.5 me/kg cl-amphehmine. Emply circles ( f S.E.M.) rrprcsent responses per minute. Control

pcrformancr

which differctl

(f

S.E.M.)

Gpnific;ln!ly

rills meeting Ihis minimum

for d-;mlphct;mlinc

from tl-:lmphctaminc rcquircmcnt

is shown on he

rcqxmding.

Icf~ of the figure. and for sllinc on the righl. Alrlcrihks reprrscnt

Only four rah complcbJ

scorek

II) responses after I.6 mg/kg raclopridc. The numhr of ;tllcr C;IC~ LIOW of YM INISI%crc WVCII. sis. five ,IIIJ / ~hrcc. rcspcctivull. and al’kr SKF 83% \c‘-.en. wcii. six iiiid 4x.

strongly

rcduccd rcsponsc rate. and a number of rats

failed to meet the minimal

rcsponsc rcquiremcnts

(ta-

bie 2).

t-‘lh.4_‘,

-- I I.20

I” l1.~1lllll t-(5..;5) = l-t.h.3 1’ .. 11.1111111 l’~s.llt I’

- 12.14 0.l11101

I l-l.3) 1’

-- 2.:.1-l

The pirolc

17..;J

IlII~IllI

t45..;51 I’

= IS.‘)2 ll.llll1ll

Fl-t.2h)

‘.-lS

II.\ I l5..35)

-7 Ifl.l-t

I’ -. ll.~ll~l~t t-l1.7ot I’

- 7.r, lI.lllllli

produced by quin-

cou111s

was blocked by SO pg/kg

YM

z 13.07. P < 0.002). but not by SO pg/kg

2.WO I:(_i.;5)

pg/kg)

OYl5l-2 (vchicic control: 7.0 * 3.3; quinpiroic control: SO 0 + ‘5.0: YM 001.51-2 + quinpiroic: 2.8 + 1.2; Fti.lT)

ll.lllNlt

t’

incrcasc in photocell (250

(data not shown).

However.

rca\,caicdthat the rats treated

with

SCH

direct observation SCH

233YO and

quinpiroic did not exhibit any coordinated motor activity. A marl-.zJ myocionic jerking behaviour accounted for the photoccil

counts. The

animals would remain

immobile for a period of time and then spring into the :lir. somctimcs to the 30 cm height of the activity box. This

bchaviour. c+scrvcd in ail five animals tested,

not

quantified

and the cxpcriment

was

was

terminated.

Jerking was not observed when these animals were used in the drug discrimination experiment with the same drug combination, or when administered with quinpirolc.

4.

0915 I-2

was

Discussion Littic

D,

YM

DA

question arises concerning the importance of rcccptors

in mediating

the discriminative

cf-

fccts of d-amphetamine. The prcscnt studies with quinpiroic and KU 24713 confirm earlier reports that sclectivc D2 agonists completely substitute for d-amphctamine (Arm. IYXX; Niclscn et al.. 1YXY). Moreover, the compictc antagonism of d-amphetamine discrimination

OYlSI-2 (3) ability of quinpiroic \‘M

amphctaminc. SCH weak attenuating cffccts.

by raciopridc and YM 00151-2 is consistent with prcviBoth

drug

combinations

ous findings with raclopride and other selective D, antagonists (Nielsen and Jcpscn, lYX3; Amt. 1988; Niciscn et al., 1YXY). l‘hc role of D, DA receptors in the d-amphetamine discriminative cue is less clear. Both SCH 23390 and SKF 83,566 potently bioc!ted d-amphetamine discrimination. The findings with SCH 23390 confirm earlier reports

(Nielsen

and Jepscn.

1YXS; Arnt,

108X; Exner

ct al.. 19X9: Nielsen et al., IYXY). In contrast to the cffccts obsclvcd with D, agonists, the scicctivc D, agonists SKF 3X3Y.3 and SKF X12Y7 failed pictciy substitute for d-amphetamine. Similar

to comfindings

have been prcviousiy observed with these compounds and other dcrivativcs such as SKF W12h and SKF 7.5070 in animals trained to discriminate d-amphetamint from saiinc (Amt. IYXX; Nielsen ct a]., IYtlY). T~ICSC

findings indicate that both D, and D,

rcccp-

IY7

tors are involved in the d-amphetamine discriminative role seems to be

effects tha1t those produced by a large increase in DA rclciisc folk%ing d-amphetamine (0.5I.() mg/kg) ad_

different. Stimulation of D, receptors appears to play a primary role, while activation of D, receptors may be

ministration. We have examined whether SKF ,%l?Y(j can gcncralisc to iI Iowa dose of d-amphetamine by

cue although their

a IWWSS~~ amphetamine with

not sufficient discrimination. This

condition for didea is consistent

but

the recent

role for D, certain D,

precise functional

hypothesis

receptors

concerning

in the functional

an ‘enabling’ expression

of

retraining

some of our animals to discriminate

mg/kg d-amphetamine from saline. All animals which learnt this ta;ik responded

().I’5

three of the almost

en-

effects

tirely on the drug lever after 0.5 mg/kg SKF 8l~Y7 (Furmidge. 1900). This finding would suggest that the

(Clark and White. 1087; Waddington and O’Boyle. lYt(Y for reviews). Howcvcr. a number of factors must

low level of drug lever responding observed after SKF X12Y7 in the 0.5 mg/kg d-amphetamine study was not

be considered before the present findings can be intcr-

the result of random responding. However. these preliminary findings should be interpreted cautiously since

receptor-mediated

bchavioural

prcted in this mannz. It might be argued that rhe failure

of SKF

X-303

it

significant

peripheral

component may underlit

the

and SKF 75670 to generalise to d-amphetamine is due to the partial agonist activity of these compounds at D,

stimulus properties of low doses of d-amphetamine (Colpaert et al.. lY76: Stolerman and D’Mcllo. IYXI ).

receptors regulating adenylatc cyclase activity (Setler et

This

al.. 1078; Arnt ct al., 198X; Niclscn et al., IYXY). Such a pharmacological profile has been suggested by certain

whether centrally administered D, agonists can substitute for low doses of d-amphetamine. It should he noted that partial substitution of about 50c; has been

behavioural

studies;

for example, high doses of both

problem

can he circumvented

by determining

compounds partially inhibit mcthylphcnidate-induced gnawing in mice (Nielsen et al.. IYXY). Howcvcr. in the

obsc~vcd with 3X3Y3 and SKF

prcscnt study SKF

inability of the drug. In contrast. partial D, DA agonists can reduce, and partially substitute for. the d-

nate 1.0 mgjkg d-amphetamine from saline (unpuhlistled findings qu~tcd in Nielsen and Scheel-Kruger. IYtiS). Clearly. all these findings emphasisc that the precise role of D, receptors in d-amphetamine discrim-

amphctaminc discriminative cut (Exner et al.. 1081); Furmidgc. 1900). Nielsen and colleagues ( lW9) oh-

ination is not yet known. l‘lie ilhility of quinpirotc

served

amphetamine was blocked by the selective D, antagonist YM 0915 I-2. However. while SCH 23390 com-

d-amphetamine

38.393 not only failed to mimic the

cue but also did not reduce discrim-

very minor

inhibitory

effects

(approxima1ely

15%) with SKF 383Y.7 and some inhibition (approximately 30%) with one of two tcstcd dosc~ of SKI; 7Sfr70. These

investigators

stated that 1he partial ago-

nist action of these compounds alone cannot explain their failure to substitute for d-amphctaminc. since the full D, agonist SKF Xl37 also failed to c~n~~plctcly gencralisc to d-amphetamine. However. Arnt et al. (lYX7). in contrast to Nielsen and colleagues,. hav’e

centrally injected fenoldopam. SKF 75670 in animals trained to discrimi-

plctcly

hlockcd 1hc cueing mine. a higher dose of this mally influcnccd quinpirrrlc collcagucs ( lYS9) reported

to

substitute

for

d-

propcrtics of d-amphetaD, antagonist only minisubstitution. Nielsen and no inhibi1ion of pcrgolidc

substitution for d-an~phctan~inc by SC‘H 33YO. The failure of SCH 233YO to bhrck D, agonist substitution (Or d-~~n~pl~ctamirIcconlrasts with the inhibitory effect

at D, receptors regulating adenylatc cycla~e activity. exhibitmg similar intrinsic activity to SKF 3S3Y3. Morc-

of this drug on the loccm~~[or stiniul~ilion produced I>! [hc ~;II~IC compounds in nr)rmal ra1s (Mailman et al.. IYH4: PupI1 et al.. IYSS: Nielsen et al.. IYSY) and in

over, Arnt and colleagues ( I’IXrO hits csprcsscd rcscI~;I-

animals

tions

amphe1amine (present findings). Thus. there appear to 11~ diffcrenccs in the dopamincrgic mechanisms vvhich

reported that SKF

in relating

determined

X1207 illso acts as i1 partial agonist

the intrinsic

activity of D,

agonists

in the adenylate cyclasc model to theit

behaviourat effects. A precise understanding in d-amphetamine

of the role of D, receptors

discrimination

cated by other findings.

Although

is further SKF

Xl37

complifailed to

completely substitute for d-amphctam1ne. it did sipnificantly increase drug tevler responding (see atso Nielhcn et al.. IYXY). In both Nielsen’s and the present study. the effects of higher doses of drug could not be examined due to the marked response disruption.

Howcv,cr.

the lcvcl of drug lever responding did appear to qmp1OtC riltllCr

The

1llilll SllOW il lY;lSl~ll~lt~lC

IL!lCVi)llCC

possible thul I>,

Of

this

ilgOlliStS

ClOSC

del~elldellcy. It i5

which

liavc

Illr)l’C Irllt~tlC

stinnrlu5

periodic

d-

underlie the mo1or stimulatory effects of D, agonists i1nd their cueing properties. This idea is supported by cl0 I-l~It potcntiother findings. Dopamine D, iIgC)lliStS agonists to gcncratisc to date the ability of D, amphetamine. despite enhancing their unconditioned behavioural effects (Nielsen et al.. ll~)sl~):l-%rmidge. l”)Y()). M(rreover. the discrimimuive effects of il pOSt%‘llaptic

;~ctiv;~1ing

iininjills

[luined

dose of the D, agonist ( - )-NPA (in 10 discriminate this drug from s,alinc)

;lrc not [Jlockcd t>y D, ilntiIgonists (Arnl. lW8). Nielsen and colleagues (

ln light

of thcsc findings,

Illa!:

~ll~~~~\Jilll~lll i5 llllClCill~.

produce

rcccivcd long-tam

tiylj1

~~)L~pling l~~1w~cn

II, and 0,

IlWC

;l

rccclnors. ‘wlicreas

Acknowledgements

it is puzzling that enccs ~-ilmp~l~t~~nli~~~.

of D, receptors influnot quinpirolc or pergolidt’.

11~~~~~~1~~

hut

trained to discriminate ds~l~~tit~ti~)~l in :tIliIlXllS ;m~phctaminc from saline. Niolscn and Schccl-Kriigcr

f Ic)SXl spc‘Clkltc.

‘that

at some point

in the chain of

synap~s involved in CNS-stimulant CUCS. D- 1 rcccptars may bc prccc‘ding D-2 rcccptl::s,‘. We interpret this hypothesis in the followin g w;I~: rclcitsc of DA by d-~~rn~b~t;~rnin~ may only intlucncc the population of D, rcwptors critical for the pcrccption of the cut’ f~~l~~)~v~~~g ~~~tiv~~ti~)~~ of .u~~str~~i~l’ D i :i‘eptors. Blackrfccptors would prccludc p~rc~pti~)n of

;rJe of D,

d_~I~~i~~l~t~ln~i~~ 3incc no D, rcccptor Sti~~ulil?i(~n would occur. On the other hand, the cffccts of selective D, aponi3ts would not bc inlluenccd. 3incc D, rcccptor btc~ckadc would not intlucncc direct 5timulaticm of ‘downstream’ DZ rcccptor sites. Howcvcr. although this is an interesting attempt to account for the drug discrimination data. thcrc is at present no anrrtomical cvidencc supporting this form of neural arrangcmcnt i

Furmidgc. lYY1) for further dlscrlssion). Although wc obsc~cd th.it the !~)~l)n~~~t~~r stimula-

SW

tory effect of quinpirt~l~ in our dis~rimin~ti~~n rats was blocked by SCH 233YO. the resulting b~h~lvi[~ur was clo~ly not normal. Animals exhibited strong myoclonic jerks during the time that they wcrc othcrwisc immobile. This behaviour wits not rcportcd by Nielsen and ~llcagua (1YSY). who used drug naive rats. or by various other investigators and, thcrcforc. may bc rclatcd to the fact that our animals had been receiving long-term periodic injections of d-amphctaminc. However, Waddington and colleagues have observed myocionic jerks in normal animals receiving ;f combingtion of D, antagonist lSCH 233YO or R-SKF and sefectivc D, agottist (RU 34113 and LY (~lddingt~~n

ct-al..

19&i.

The authrrr\ yratcfully acknowledge Chris Martin for technical ar+t;rncc. and IIr. Paul Owrton and Nancy Retry for comments on lhiz manuscript. The cornpanic\ ;tstcrilrkcd in the drugs section are th;rnkcd for their kind gift>. Thi> &c)rk war supported by research gr;mtr frtm the Science ;mJ Engineering Research Council. Parkinzon’s Diseazc Society. University of Reading Research Endowment Fund .tnrl the North Atlantic Treaty ~r~~inis~til~n. L.F. was the recipient ctf ;I SERC‘ studentship and M.E. a s~h~~l~lrshipfrom the German Ac;rticmic Exchange. D.C. is currently a SERC Advanced Rcx~rcl; Fcllo\t and h4.E. is ihe recipient of a Wrllcome Prize >tutJcntship.

83566) l&Qj()t)

IYXH; set also Grab~~wska-

And&n and And!%, 1983, 19871. Strangely, myocionic jerks wcrc not obscrvcd during the drug discrimination study with SCH IWO and quinpirolc. 12 this c;~sc, animals wcrc injcctcd with the drugs and remained in

their home cage (with one other rat) before

bcitlg

placed in the operant chamber. During the activity study. the rats were injected with the drugs ;tnd rcplaced into the open-topped activity hoxcs. it is thcrcfort possible that an ~nvir~~nrn~nt~l influence plays ;t Part in the ~xpr~ssi(~li of this b~h~vi~~ur, ;i pnint whicll merits inv~stig~ti[)n.

References ,1rnt. J.. I%#. The discriminative stimulus properties of the D-l ;tgonisl Sk&F .3r(3Y3and the D-2 agonist ( - 1-NPA are mediated 1~)zcpxutr mcchanibm5. Life Sci. 42. 565. Amt. J.. J. ltyttcl and E. M&r. IYXX. Inactivation of dopamine D-i or D-2 receptors ~iff~r~nti~lly inhibits stereotypies induced by ~~~p~~~~~i~~e atxmists in rats. Eur. J. Pharmacol. 1%. 37. Amt. 1.. J. ffyttel and J. Prrregnard. IYK7. Dopamine P-1 ieceptor aptmists combined with the D-2 agonist quinpirole facilitate the espressitm of oral strret~typrd hehaviour in rats. Eur. J. Phermacol. 1.13. 137. Barone. P.. T.A. Davis. AR. Brnun mxl T’.N. Chase. 19X6, Dopaminc&c mcch;mismh and motor function: Characterization of D-l ;tnd D-3 rlopaminc receptor interactions. Eur. J. Pharmacol. 123. IOY. (‘adson. J.11.. D.A. Bergstrom and J.R. Walters, IYX7, Stimulation of both D, und D2 dopamine receptors appears necessary for full cxprc5sion of postsynnptic effects of dopamine agonists: a neuroph~s~~~l(~~i~~ii study. Brain Res. ItI@. 205. Clark. D. and F.J. White. lYX7, Review: Dl ~(~p~rnine receptttr The search for a function: A critical evaluation of the DI/D2 rktpamine receptor cl~ssifie~ili(?nand it’s functional implieslions, Synapse I. 347. (*olpaert. F.C., J.J.M.D. Kuyps. C.J.E. Nicmegoers and P.A. Janssen. lY7h. Dixriminative stimulus properties of iI low dl-amphetamine dooc. Arch. In!. Ph;rrmacodyn. 223, 34. Costall. B.. C.D. Marsden. R.J. Naylur and C.J. Pycock. lY77. Stereotyped bchaviour patterns and hyperactivity induced by am phetaminr and apomorphinc after discrete O-hydroxydopamine Icbions of cxtrdpyrar,..id;il and mesolimbic nuclei. Brain Reb. 123. HY. Exner. M,. L.J. Furmiclge and D. Clark. IoXci. Inhibitory eff&s of pxtial D2 dopzmine receptor agonists on the ~-amphetamine ~is~rimin~iiive cue. Behav. Ph~rm~c~i. 1. 101. Extanco, K. and A.J. Gttudic. IYXI. lnt~r-~lnimui dldory cues in ctperant drug ctiscri~ni?~tion procedures in tats, Psychoph~rm~colyy 73. 3h.f. Furmid~c. L.J.. IYYO. Effects of Partial Dopamine D2 Receptor Agonists on d-Amphetamine-induced Behaviour (Ph.D. Thesis. University of Reading. U.K.). Furmid~e. L.J.. M. Exncr and D. Clark. IYXYa. Involvement of DI and D:! dopamine receptors in the d-amphetamine discriminative cue. J. P~ychophami;lcol. 3 I P. Furmidge. L.J.. M. Exncr and 0. Clark. IOhYh. The cl-amphetamine discriminative cue: Involvement of Dl and D2 dopamine receptors. Bchav. Pharnwzol. I ffiuppl. I). IO. Gcrshanik, 0.. R.E. Heikkiln and R.C. Duvoisin. l