European Journal of Pharmacology, 213 (1992) 251-258
251
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52353
Two directions of dopamine D 1 / D 2 receptor interaction in studies of behavioural regulation: a finding generic to four new, selective dopamine D 1 receptor antagonists S i o b h a n A. D a l y a n d J o h n L. W a d d i n g t o n Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland Received 21 October 1991, revised 10 December 1991, accepted 24 December 1991
A range of new, chemically distinct D 1 dopamine receptor antagonists, SCH 39166, NO 756, A-69024 and BW 737C, were studied for their effects on behavioural responses to the selective D 2 agonist RU 24213. Each D 1 antagonist not only blocked typical sniffing and locomotor responses to RU 24213 but also released atypical myoclonic jerking behaviour, while the selective D 2 antagonist YM 09151 blocked these typical responses but did not release jerking. The rank order of effectiveness of these D 1 antagonists to release such D 2 agonist-induced jerking was similar to that of their selectivities as D 1 antagonists; also, the action of BW 737C showed complete enantioselectivity, the inactivity of its R-antipode BW 736C paralleling enantioselective blockade of D 1 but not D 2 receptors. It appears that while tonic activity through D 1 receptors is necessary for the expression of typical D2-stimulated behaviour, via well-known cooperative/synergistic D l : D 2 interactions, D 1 tone also normally inhibits, via oppositional D I : D 2 interactions, the expression of atypical D2-stimulated behaviours such as jerking. Oppositional D I : D 2 interactions are evident using all of the classes of selective D 1 antagonist currently known, and appear to constitute another general mode of dopaminergic regulation. Dopamine D 1 receptors; Dopamine D 2 receptors; Dopamine D1/D 2 receptor interactions; Behaviour; Jerking; SCH 39166; NO 756; A-69024; BW 737C
1. Introduction The psychopharmacological and other effects of SCH 23390 have, since its introduction as the first selective D 1 dopamine (DA) receptor antagonist (Hyttel, 1983; Iorio et al., 1983), changed radically our perspectives on the functional roles of D A receptor subtypes in the regulation of psychomotor behaviour. It is now recognised at many levels of enquiry that D 1 and D 2 receptors often do not exert independent roles but rather interact fundamentally to determine the totality of DAergic function (Waddington and O'Boyle, 1987, 1989; Arnt, 1987; Clark and White, 1987; Waddington, 1989). Subsequently, in studies seeking to clarify further the role of D t : D 2 interactions in the regulation of behaviour, we have reported data consistent with two forms of such interaction: one cooperative/synergistic that appears to regulate typical DAmediated behaviours, the other oppositional that appears to regulate certain atypical DAergic responses
Correspondence to: J.L. Waddington, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland~ St. Stephen's Green, Dublin 2, Ireland.
(Murray and Waddington, 1989a); for example, SCH 23390 given prior to the selective D 2 agonist LY 163502 blocks typical sniffing and locomotor responses but releases episodes of atypical myoclonic jerking (Murray and Waddington, 1989b). However, the vast bulk of the above studies on D ~ : D 2 interactions has derived from the use of one selective D 1 antagonist, the benzazepine SCH 23390. T h e r e is clearly some considerable danger in elaborating new concepts and then seeking to refine them further all on the basis of essentially a single drug, but over this period no other class of D 1 antagonist has been available (Waddington and O'Boyle, 1989). Because of the therapeutic potential of such agents as antipsychotics (Waddington, 1988; Waddington and Daly, in press), several new, chemically distinct compounds have recently been identified: SCH 39166 (Chipkin et al., 1988), N O 756 (Andersen et al., 1988), A-69024 (Kerkman et al., 1989) and BW 737C (Riddall, 1992). It is therefore critical to establish the extent to which they might show properties similar to SCH 23390, particularly in the behavioural paradigm exemplified above which indicates a more complex profile of dual D I : D 2 interactions in the regulation of distinct elements of typical and atypical behaviour. Thus, to elabo-
252 rate further on the basis of such effects, we have utilised behavioural responses to the selective D 2 agonist R U 24213 (Euvrard et al., 1980; Pugh et al., 1985) and have studied the effects of SCH 39166, NO 756, A-69024 and BW 737C on such responses in comparison with SCH 23390 and the selective D 2 antagonist YM 09151 (Terai et al., 1989).
2. Materials and methods
2.1. Behavioural studies Young adult male Sprague-Dawley rats (125-365 g; Biolabs, B a l l i n a / U C D ) were used in all experiments. The rats were housed in groups of five per cage with food and water available ad libitum, and were maintained at 21 + I°C on 12/12 h (6:00 a.m. on; 6:00 p.m. off) light/dark schedule. On experimental days they were placed individually in perspex cages 52 x 39 x 18 cm and left undisturbed for a habituation period of 2.5 h. Behavioural assessments were carried out in a manner similar to that described previously (Murray and Waddington, 1989b; Daly and Waddington, in press). Immediately before and at intervals after injection of drug or vehicle, animals were assessed using a rapid time-sampling behavioural check list technique. For this procedure, each rat was observed individually for 5 s periods at 1 min intervals over 5 consecutive min, using an extended behavioural check list. This allowed the presence or absence of the following individual behaviours (occurring alone or in combination) to be determined in each 5 s period: stillness (St, motionless with no behaviour evident); sniffing (Sn); locomotion (L); rearing (R); grooming (Gr, of any form); intense grooming (a characteristic pattern of grooming of the face with the forepaws followed by vigorous grooming of the hind flank with the snout); vacuous chewing (not directed onto any physical material); chewing (Ch, directed onto any physical material); jerking (J, myoclonic movements of the limbs or whole body). When evident, jerks were quantified further using the following scale: 1 = small, 2 = medium; 3 = large, based on amplitude of movement and extent of bodily involvement (see Results). After assessment using the behavioural check list, animals were evaluated using a conventional 0 - 6 point stereotypy rating scale: 0 = asleep or inactive; 1 = episodes of normal activities; 2 = discontinuous activity with bursts of prominent sniffing or rearing; 3 = continuous stereotyped activity such as sniffing or rearing along a fixed path; 4 = stereotyped sniffing or rearing fixated in one location; 5 = stereotyped behaviour with bursts of licking or gnawing; 6 = continuous licking or gnawing. This cycle was repeated at 10 min intervals. Rats were used on
two occasions only, separated by a drug free interval of at least one week; on each occasion rats were randomly allocated to one of the various treatment groups. All assessments were made by an observer unaware of the treatment given to each animal.
2.2. Radioligand binding studies Using methods similar to those described previously (Murray and Waddington, 1989b; Daly and Waddington, in press), striata from similar male Sprague-Dawley rats were homogenised in 30 volumes of 50 mM Tris-HC1 buffer, pH 7.6 at 25°C, and centrifuged at 10000 x g at 4°C for 5 min. The pellet was twice resuspended, diluted and centrifuged as above. The membrane preparation was finally resuspended at 4 - 8 mg original wet weight/ml in Tris-HCl buffer containing: 120 mM NaC1, 5 mM KC1, 1 mM MgCI2, 2 mM CaC12, 0.2 mM Na2S205 (as antioxidant) and 1 0 / z M pargyline (as monoamine oxidase inhibitor). The binding of [3H]SCH 23390 (83 Ci/mmol, Amersham) to D 1 receptors was determined by incubating 0.5 ml of membrane suspension with 0.3 nM ligand and unlabelled drugs at 37°C for 20 min in a total volume of 1 ml. Specific binding was defined as that displaced by 100 nM piflutixol (Lundbeck), and typically represented 93% of total binding. Incubations were stopped by filtration through G F / B filters, followed by two 8 ml washes with ice-cold buffer. Radioactivity trapped on the filters was quantified by liquid scintillation spectroscopy after addition of 5 ml of liquiscint (Med labs) using a LKB 1214 Rackbeta counter with 51% counting efficiency for tritium. The binding of [3H]spiperone (15 Ci/mmol, Amersham) to D 2 receptors was determined using membranes prepared as above. Incubations contained 0.5 ml of membrane suspension with 0.18 nM ligand and unlabelled drugs in a total volume of 5 ml. Specific binding was defined as that displaced by 1 /zM domperidone (Janssen) and typically represented 82% of total binding. Incubation and filtration were as described above.
Z3. Drugs The following investigational drugs were used: R U 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine; Roussel-UCLAF, France); SCH 23390 (R7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-lH-3-benzazepine; Schering-Plough, USA); SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo[d]naphtho-[2,1b]-azepine; Schering-Plough, USA); NO 756 ([+]-8-chloro-5[2,3dihydrobenzofuran-7-yl] 3-methyl-2,3,4,5-tetrahydro1H-3-benzazepine; Novo, Denmark); A-69024 (112-
253
bromo-4,5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2methyl-l,2,3,4-tetrahydroisoquinoline; Abbott, USA); BW 737C (S-6-chloro-l-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline and its R-antipode BW 736C; Wellcome Foundation, UK); YM 09151 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide; Yamanouchi, Japan). RU 24213, SCH 23390 and BW 736C/737C were dissolved in distilled water; SCH 39166, NO 756 and A-69024 were dissolved in a minimum of acetic acid and made up to volume with distilled water; YM 09151 was dissolved in a minimum of dilute HC1 and made up to volume with distilled water. All drugs were injected subcutaneously into the flank in a volume of 2 ml/kg, with antagonists or respective vehicles given 30 min prior to agonist challenge.
2.4. Data analysis From the application of the behavioural check list, the total 'counts' for each individual behaviour was determined as the number of 5 s observation windows in which a given behaviour was evident, summed over a 1 h period, and expressed as means + S.E.; stereotypy scores were averaged over the 1 h period and expressed similarly. These data were then analysed using analysis of variance (ANOVA) or the Kruskal-Wallis non-parametric ANOVA, followed by Student's t-test or Mann-Whitney U-test, respectively. Data from radioligand displacement experiments were analysed by a computer-assisted non-linear iterative curve fitting procedure (Barlow, 1983). The resulting IC50 was converted to a K i value using the Cheng-Prusoff equation; K i = IC50/(1 + C / K D) where C is ligand concentration and K D is the apparent dissociation constant from saturation studies as described elsewhere (Daly and Waddington, in press).
3. Results
3.1. Behavioural studies When given alone, the selective D 2 agonist RU 24213 (0.5-15.0 mg/kg) reduced episodes of stillness and grooming, and induced dose-dependent increases in sniffing, locomotion and, occasionally, rearing; minimal chewing but no vacuous chewing, intense grooming or jerking was evident (table 1). Low scores on the stereotypy rating scale indicated that those behaviours stimulated were not being expressed in a classically stereotyped manner. On selecting as a challenge dose of RU 24213 that which resulted in the highest mean score on the stereotypy rating scale (15.0 mg/kg), its actions to decrease stillness and to induce sniffing and locomotion were readily and dose dependently blocked by pretreatment with the selective D 2 antagonist YM 09151 (0.005-0.5 mg/kg); the result was a quiescent animal, with no behaviour other than a trivial level of chewing emerging to fill this behavioural void. These typical sniffing and locomotor responses to RU 24213 were also readily reduced by the selective D~ antagonist SCH 23390 (0.01-1.0 mg/kg) but a quiescent state did not result. Rather, such pretreatment with SCH 23390 dose dependently released episodes of myoclonic jerking; these movements ranged from small but evident jerks of the head/upper body, through more generalised involvement of other body regions, to prominent jerking of the whole body with vigorous limb movements that could propel the animal upwards into the air from the floor of the cage (table 1, fig. 1). These jerks often had a brief 'activating' effect on animals in terms of the re-emergence of some episodes of sniffing over the first few seconds of each post-jerk period, and this phenomenon disrupted somewhat the dose dependency of the reduction in RU 24213-induced sniffing associated with SCH 23390 pretreatment; no such effect was evident in terms of RU 24213-induced locomotion,
TABLE 1 Induction of behaviours by RU 24213. Data are means ± S.E. of behavioural counts or stereotypy scores for n = 8 animals per group. Dose mg/kg
St
Sn
L
R
Gr
Ch
J
Stereotypy score
0.4±0.3
1.0± 0.6
2.3±0.7
1.3±0.6
0.0±0.0
0.4±0.1
0.8±0.5 2.8±0.9 a 9.5±2.2 a 8.1±1.5 a
1.4±0.9 2.9±0.8 4.0±1.3 1.9± 0.4
0.4±0.2 a 0.6±0.4 0.3±0.2 a 0.1±0.1 a
1.0±0.5 1.9± 0.6 1.9±0.5 0.6±0.2
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.2 1.5±0.1 a 1.6±0.1 a 1.9±0.1 a
~hic& -
17.5±2.6
9.8±2.4
RU24213 0.5 1.5 5.0 15.0
20.5±3.3 7.5 ±3.5 a 0.8±0.3 a 0.3±0.2 a
a p < 0.05 vs. vehicle
8.5±2.9 23.5±2.6 a 28.0±0.6 a 29.3±0.3 a
254 TABLE 2 Effects of YM 09151 and SCH 23390 on behavioural responses to RU 24213. Data are means± S.E. of behavioural counts or stereotypy scores for n = 8 animals per group. Drug
Dose mg/kg
St
RU24213 +YM09151
15.0 0.005 0.05 0.5
0.5±0.2 5.9±2.0 22.6±2.0 24.1±1.4
RU24213 +SCH23390
15.0 0.01 0.1 1.0
a
L a b b b
0.4±0.3 a 1.4±0.5 8.1±2.4 b 9.6±2.4 b
16.9±2.1 6.1±1.7 1.6±0.7 1.1±0.3
a b b b
12.8±1.9 a 7.1±2.1 3.0±2.3 b 0.8±0.5 b
R
Gr
Ch
Stereotypy score
1.3±0.6 1.8±0.9 0.3±0.3 0.1±0.1
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.3±0.3 1.6±0.6 1.1±0.3 b 0.1±0.1
1.9±0.1 1.2±0.2 0.2±0.1 0.1±0.1
3.1±0.8 a 4.4±1.2 a 2.1±0.9 1.3±0.6
0.1±0.1 0.0±0.0 0.1±0.1 0.0±0.0
0.5±0.4 1.3±0.8 1.1±0.4 0.4±0.3
1.6±0.1 a 1.5±0.1 0.9±0.2 b 0.7±0.2 b
a b b b
p < 0.05 vs. vehicle; b p < 0.05 vs. RU 24213 alone.
w h i c h w a s e s s e n t i a l l y a b o l i s h e d by S C H 23390 ( t a b l e 2, fig. 1). E a c h o f t h e n e w s e l e c t i v e D , a n t a g o n i s t s S C H 39166 ( 0 . 1 - 1 0 . 0 m g / k g ) , N O 756 ( 0 . 0 1 - 1 . 0 m g / k g ) , A - 6 9 0 2 4 (1.0-25.0 mg/kg) and BW 737C (0.2-5.0 mg/kg) c a u s e d r e d u c t i o n s in R U 2 4 2 1 3 - i n d u c e d s n i f f i n g a n d l o c o m o t i o n w h i l e r e l e a s i n g m y o c l o n i c j e r k i n g . I n all i n s t a n c e s t h e r e d u c t i o n in l o c o m o t i o n w a s d o s e - d e p e n d e n t , w h i l e t h a t f o r s n i f f i n g w a s a g a i n d i s r u p t e d by b r i e f a c t i v a t i o n in t h e i m m e d i a t e p o s t - j e r k p e r i o d s , as d e t a i l e d a b o v e ; this p h e n o m e n o n was particularly p r o m i n e n t f o r S C H 39166 a n d B W 737C. A t t h e d o s e s u s e d , S C H 39166 a n d B W 7 3 7 C r e l e a s e d t h e g r e a t e s t n u m b e r o f j e r k s w h i l e A - 6 9 0 2 4 w a s less e f f e c t i v e ; N O 756 s h o w e d an i n t e r m e d i a t e l e v e l o f activity, s i m i l a r to t h a t o f S C H 23390, T h e a c t i o n s o f B W 7 3 7 C t o r e d u c e R U 2 4 2 1 3 - i n d u c e d s n i f f i n g a n d l o c o m o t i o n a n d to re-
lease episodes of jerking showed complete enantioselectivity, its R - a n t i p o d e B W 7 3 6 C (5.0 m g / k g ) b e i n g e n t i r e l y w i t h o u t e f f e c t ( t a b l e 3, fig. 2). The nature of the dose-dependent release of jerking to R U 24213 by e a c h o f t h e five s e l e c t i v e D 1 a n t a g o nists was e x a m i n e d f u r t h e r . C o m p a r i s o n o f s c o r e s for t h o s e j e r k s m a n i f e s t e d at e a c h d o s e o f t h e D 1 a n t a g o nists i n d i c a t e d t h a t i n c r e a s e s in b e h a v i o u r a l c o u n t s w e r e n o t a c c o m p a n i e d by any g e n e r a l i n c r e a s e in severity o f j e r k i n g m o v e m e n t s ( o v e r a l l m e a n s c o r e 1.9 + 0.1; r a n g e 1 . 4 - 2 . 5 ) ; i n d e e d , t h e m o r e f r e q u e n t t h e jerks, t h e less s e v e r e t h e y t e n d e d to be.
3.2. Radioligand binding studies B o t h S C H 39166 a n d N O 756 d e m o n s t r a t e d h i g h affinity a n d s e l e c t i v i t y for D 1 r e c e p t o r s , c o m p a r a b l e to
TABLE 3 Effects of SCH 39166, NO 756, A-69024, BW 736C and BW 737C on behavioural responses to RU 24213. Data are means± S.E. of behavioural counts or stereotypy scores for n = 6-16 animals per group. Drug
Dose mg/kg
St
RU24213 +SCH39166
15.0 0.1 1.0 10.0
1,0±0.6 13.1±2.7 10.1±2.7 8.3±2.5
a b b b
4.9±0.7 0.6±0.5 0.6±0.3 0.8±0.5
RU24213 +NO756
15.0 0.01 0.1 1.0
0.6±0.3 3.3±1.8 11.5±2.7 12.4±1.8
a b b b
11.4±1.6 a 9.3±2.9 2.0±0.8 ~ 0.4±0.2 b
RU24213 +A-69024
15.0 1.0 5.0 25.0
0.9±0.3 a 3.3±1.3 10.5±2.6 ~ 14.8±2.0 b
7.5±1.6 a 5.8±1.5 2.1±1.1 b 0.1±0.1 b
RU24213 +BW 736C +BW 737C
15.0 5.0 0.2 1.0 5.0
0.3±0.1 0.4±0.2 10.3±2.8 9.3±1.5 11.0±0.3
a
L
a a ~ b b
p < 0.05 vs. vehicle; b p < 0.05 vs. RU 24213 alone.
11.5±2.0 11.4±3.5 5.1±2.6 2.9±1.2 1.5±0.9
a b b b
a a b b
R
Gr
Ch
Stereotypy score
0.5±0.3 0.6±0.4 0.6±0.4 1.1±0.5
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
1.0±0.6 0.1±0.1 0.1±0.1 0.0±0.0
1.6±0.1 0.7±0.2 0.7±0.1 1.0±0.1
1.9±0.5 a 4.3±1.3 a 0.4±0.2 1.4±0.4 a
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.3 0.5±0.2 0.4±0.2 0.3±0.2
1.7±0.2 a 1.5±0.2 0.7±0.1 b 0.7±0.1 b
0.9±0.4 0.8±0.5 0.5±0.4 1.4±0.6
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.2 0.5±0.3 0.3±0.2 0.3±0.2
1.7±0.1 a 1.0±0.2 0.7±0.1 b 0.5±0.5 b
1.0±0.2 1.5±0.4 1.0±0.5 1.9±0.9 0.4±0.3
0.0±0.0 0.1±0.1 0.0±0.0 0.0±0.0 0.0±0.0
0.1±0.1 0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
1.8±0.1 1.9±0.1 0.7±0.2 0.8±0.1 0.6±0.1
a b b b
a a b b b
255
"t
YM 09151
Sniffing
II
il
11,,
oli,.
2O
10
0
TABLE 4
SCH 23390
Jerking
15
10
t
5 0
m
__
RU V 15 15 15 15 YM V V .005 .05 .5
i
--'r--
|i
Displacement of [3H]SCH 23390 and of [3H]spiperone from striatal D l and D 2 receptors, respectively, by investigatory agents. Values are geometric means of at least three independent determinations, each performed in duplicate. Drug
K i (nM)
D 1/D~
[3H]SCH 23390 (D l)
[ 3H]spiperone (D 2)
16 634 6884 0.18 0.72 0.18 24.5 0.31 895
244 0.23 846 998 782 1343 36.5 2410
RU 24213 YM 09151 SCH 23390 SCH 39166 NO 756 A-69024 BW 737C BW 736C
68 29930 0.0002 0.0007 0.0002 0.018 0.008 0.37
RU V 15 15 15 15 SCHV V .01 .1 1.0
Fig. 1. Behavioural counts for sniffing and jerking responses to RU 24213 (RU; 15.0 mg/kg) after pretreatment with vehicle (V), YM 09151 (YM; 0.005-0.5 mg/kg) or SCH 23390 (SCH; 0.01-1.0 mg/kg). Data are means_+S.E, of n = 8 animals per group, a p < 0.05 vs. vehicle; * P < 0.05 vs. RU 24213 alone.
SCH 23390. A-69024 showed the lowest D 1 receptor affinity and selectivity of the new antagonists examined, while BW 737C showed high affinity but somewhat reduced selectivity for D1 receptors; these propSCH 39166
erties of BW 737C were characterised by essentially complete enantioselectivity, its R-antipode BW 736C showing negligible D i receptor affinity and selectivity (table 4). The rank order of affinity for D 1 receptors was N O 756 = SCH 23390 -- BW 737C -- SCH 39166 >> A-69024, while the rank order of selectivity for D 1 vs. D 2 receptors was N O 756 = SCH 2 3 3 9 0 - - S C H 39166 > BW 737C > A-69024. In comparative studies, the reference compounds R U 24213 and YM 09151 were confirmed to show selective affinity for D 2 receptors.
NO 756
A-69024
BW 736/7C
Sniffing
linn
:t10 ~ i l l l o
""
Jerking
.
RU V SCH V
.
.
.
_
15 15 15 15
RU
V
NO V
.1 1.0 10
V
15
15 15 15
V .01 .1 1.0
_
i
.
RU
V
15 15 15 15
A
V
V
.
1
_
5
25
_
_
RU
V 15
BW
V
V
15 15 15 15 5
.2
1
5
R S S S
Fig. 2. Behavioural counts for sniffing and jerking responses to RU 24213 (RU; 15.0 mg/kg) after pretreatment with vehicle (V), SCH 39166 (SCH; 0.1-10.0 mg/kg), NO 756 (NO; 0.01-1.0 mg/kg), A-69024 (A; 1.0-25.0 mg/kg), the R-enantiomer BW 736C (BW, R; 5.0 mg/kg) or its S-antipode BW 737C (BW, S; 0.2-5.0 mg/kg). Data are means+S.E, of n = 6-16 animals per group, a p < 0.05 vs. vehicle; * P < 0.05 vs. RU 24213 alone.
256 4. Discussion
While the concept of cooperative/synergistic D~ : D 2 interactions in the regulation of typical DAergic behaviours has received considerable attention (Waddington and O'Boyle, 1987, 1989; Arnt, 1987; Clark and White, 1987; Waddington, 1989), it derives essentially from studies with the first selective D~ antagonist, the benzazepine SCH 23390, and its partial agonist congener SK&F 38393. Of greater concern here is the proposal that such a schema requires modification to accommodate evidence for other, atypical behaviours appearing to be regulated by distinct, oppositional D~ : D 2 interactions (Murray and Waddington, 1989a,b). Were similar results to be obtained using several new, chemically distinct selective D~ antagonists that have become available only recently, this would constitute important evidence for the generality of such a proposal and could provide much needed clues as to the nature of such processes. We find that each of a series of novel selective D~ antagonists, the benzonaphthazepine SCH 39166 (Chipkin et al., 1988), the benzofuran NO 756 (Andersen et al., 1988) and the tetrahydroisoquinolines A69024 (Kerkrnan et al., 1989) and BW 737C (Riddall, 1992), shares with SCH 23390 the following properties: (i) antagonism of typical sniffing and locomotor behaviour induced by the selective D e agonist RU 24213, via reduction of D 1 tone that is normally 'permissive' or 'enabling' for the expression of such typical D 2stimulated behaviours in accordance with cooperative D 1:D 2 interactions (Waddington and O'Boyle, 1989; Waddington, 1989); (ii) release of atypical myoclonic jerking behaviour in response to RU 24213, apparently via reduction of D1 tone that would normally inhibit the expression of such atypical Dz-stimulated behaviour in accordance with postulated oppositional D 1: D 2 interactions (Murray and Waddington, 1989a,b). Jerking was never seen spontaneously and was an extremely rare response to RU 24213 given alone or after pretreatment with the selective D 2 antagonist YM 09151. Such D 2 antagonist pretreatment acted only to block the typical sniffing and locomotor responses to RU 24213, indicating that jerking was not released by the D~ antagonists through simple attenuation of competing behaviours. The complete enantioselectivity of this effect, seen robustly with the S-enantiomer BW 737C but not at all with its R-antipode BW 736C, paralleled their enantioselective blockade of D~ but not D 2 receptors. SCH 39166 and BW 737C were the most effective releasers of jerking, and these are the two 'cleanest' of the new selective D~ antagonists; for example, they show less affinity for 5-hydroxytryptamine 2 receptors than do SCH 23390 and NO 756 (Chipkin et al., 1988; Riddall, 1992; Andersen et al., 1988), which were less effective releasers of jerking.
A-69024 showed both the lowest affinity for D~ receptors and the lowest D J D 2 selectivity ratio (see also Kerkman et al., 1989), and was the least effective releaser of jerking among the compounds examined. These data indicate an essential role for concurrent suppression of D~ receptor-mediated function in the genesis of D 2 agonist-induced jerking. The nature of this jerking response is not well understood. It seems to have been first described and so named by Grabowska-And6n and And6n (1983) as a response to the D 2 'autoreceptor' agonist B-HT 920 and to a lesser extent to apomorphine after pretreatment with reserpine. Subsequently, a similar response to such agents was noted following pretreatment with SCH 23390 and its close homologue SK& F 83566, and the possibility of a basis in D 2 stimulation during concurrent D~ blockade was considered (Waddington et al., 1986; Grabowska-And6n and And6n, 1987; Murray and Waddington, 1989b). Phenomenologically, perhaps the closest human parallel is that of sudden bodily jerks sometimes experienced on falling asleep (Oswald, 1959); D~ antagonism can induce sedation and increase sleep duration (Trampus and Ongini, 1990), hence D 2 activity under these conditions might provoke such phenomena. At the human level there is little evidence that this behaviour is related to any epileptic state (Oswald, 1959), and recent animal studies indicate D~ antagonism and D 2 agonism rather act to raise seizure threshold in a variety of convulsive paradigms (A1-Tajir et al., 1990; Barone et al., 1991). Thus, jerking might be best considered at this stage to be an episodic, atypical motor behaviour rather than a reflection of any epileptogenic process. If the behavioural data reported here are to be used to buttress and extend the concept of two directions of D~ :O 2 interaction, are distinct profiles of such interaction apparent at other levels of examination? The well-known cooperative/synergistic D 1 : D 2 interactions that regulate typical DAergic behaviours (Waddington and O'Boyle, 1989; Waddington, 1989) are readily paralleled by very similar profiles of D I : D 2 interaction in the regulation of striatal, accumbal and pallidal electrophysiology (Waiters et al., 1987; Wachtel et al., 1989); furthermore, cooperative/synergistic D~ : O 2 interactions at the neurochemical level have recently been described (Bertorello et al., 1990; Piomelli et al., 1991). Oppositional D I : D 2 interactions, which appear to regulate certain atypical DAergic behaviours such as jerking, may have a ready parallel in the opposing roles of D~ and D 2 receptors in regulating the activity of striatal adenylate cyclase (Stool and Kebabian, 1981; Onali et al., 1985), but it is only more recently that comparable electrophysiological interactions have been reported, in the ventral pallidum/substantia innominata (Maslowski and Napier, 1991); recent studies at other levels of function also indicate
257
oppositional D t :D 2 interactions, at least in the striaturn (Altar et al., 1990; Damsma et al., 1990). However, the site(s) involved in the genesis of jerking behaviour remain poorly defined, though it appears to constitute a potentially useful model for such particular DAergic mechanisms. The present data indicate two directions of D~:Dz interaction, cooperative in the regulation of typical DA-mediated behaviours and oppositional in the regulation of certain atypical DA-mediated behaviours such as jerking, to be a finding generic to all of the classes of selective Dt antagonist currently available; there appear to be distinct putative correlates of each of these two forms of D1:D 2 interaction at both the electrophysiological and neurochemical levels. What is less clear is whether DI and D2 receptors involved in cooperative/synergistic interactions are homogeneous with those involved in their oppositional counterparts. It remains possible that any such differences might represent functional distinctions between members of the families of 'Dr-like' (DIA, Dm and D 5) and 'D2-1ike' (D2L, D2s, D 3 and D 4) DA receptor subtypes identified recently in molecular biological studies; however, clarification of this issue will have to await the identification of compounds better able to discriminate between the individual members of each family (Waddington, 1991). Irrespective of this, D~:D 2 interactions do not appear to act in a uniformly cooperative/synergistic manner; their oppositional counterparts appear to act more generally than has been recognised previously, and will need to be taken into account when seeking to explain DAergic phenomena.
Acknowledgements This work was supported by the Wellcome Trust. We thank Abbott, Novo, Roussel, Schering, Wellcome Foundation and Yamanouchi for kindly making compounds available to us.
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258 behaviour induced by the D-2 agonist RU 24213, Psychopharmacology 87, 308. Riddall, D.R., 1992, A comparison of the selectivities of SCH 23390 with BW 737C for D 1, D E and 5-HT 2 binding sites both in vitro and in vivo, Eur. J. Pharmacol. 210, 279. Stool, J.C. and J.W. Kebabian, 1981, Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum, Nature 294, 366. Terai, M., K. Hidaka and Y. Nakamura, 1989, Comparison of [3H]YM-09151 with [3H]spiperone and [3H]raclopride for dopamine D-2 receptor binding to rat striatum, Eur. J. Pharmacol. 173, 177. Trampus, M. and E. Ongini, 1990, The D-1 dopamine receptor antagonist SCH 23390 enhances REM sleep in the rat, Neuropharmacology 29, 889. Wachtel, S.R., X.-T. Hu, M.P. Galloway and F.J. White, 1989, D-1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D-2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems, Synapse 4, 327. Waddington, J.L., 1988, Therapeutic potential of selective D-1 dopamine receptor agonists and antagonists in psychiatry and neurology, Gen. Pharmacol. 19, 55.
Waddington, J.L., 1989, Functional interactions between D-1 and D-2 dopamine receptor systems: their role in the regulation of psychomotor behaviour, putative mechanisms, and clinical relevance, J. Psychopharmacol. 3, 54. Waddington, J.L., 1991, The Psychopharmacology of D-1 dopamine receptors, J. Psychopharmacol. 5, 441. Waddington, J.L. and S.A. Daly, The status of 'second generation' selective D-1 dopamine receptor antagonists as putative atypical antipsychotic agents, in: Novel Antipsychotic Medications, ed. H.Y. Meltzer (Raven Press, New York) (in press). Waddington, J.L. and K.M. O'Boyle, 1987, The D-1 dopamine receptor and the search for its functional role: from neurochemistry to behaviour, Rev. Neurosci. 1, 157. Waddington, J.L. and K.M. O'Boyle, 1989, Drugs acting on brain dopamine receptors: a conceptual reevaluation five years after the first selective D-1 antagonist, Pharmacol. Ther. 43, 1. Waddington, J.L., A.G. Molloy, K.M. O'Boyle and M. Mashurano, 1986, Motor consequences of D-1 dopamine receptor stimulation and blockade, Clin. Neuropharmacol. 9 (Suppl. 4), 20. Waiters, J.R., D.A. Bergstrom, J.H. Carlson, T.N. Chase and A.R. Braun, 1987, D-1 dopamine receptor activation required for postsynaptic expression of D-2 agonist effects, Science 236, 719.
251
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52353
Two directions of dopamine D 1 / D 2 receptor interaction in studies of behavioural regulation: a finding generic to four new, selective dopamine D 1 receptor antagonists S i o b h a n A. D a l y a n d J o h n L. W a d d i n g t o n Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland Received 21 October 1991, revised 10 December 1991, accepted 24 December 1991
A range of new, chemically distinct D 1 dopamine receptor antagonists, SCH 39166, NO 756, A-69024 and BW 737C, were studied for their effects on behavioural responses to the selective D 2 agonist RU 24213. Each D 1 antagonist not only blocked typical sniffing and locomotor responses to RU 24213 but also released atypical myoclonic jerking behaviour, while the selective D 2 antagonist YM 09151 blocked these typical responses but did not release jerking. The rank order of effectiveness of these D 1 antagonists to release such D 2 agonist-induced jerking was similar to that of their selectivities as D 1 antagonists; also, the action of BW 737C showed complete enantioselectivity, the inactivity of its R-antipode BW 736C paralleling enantioselective blockade of D 1 but not D 2 receptors. It appears that while tonic activity through D 1 receptors is necessary for the expression of typical D2-stimulated behaviour, via well-known cooperative/synergistic D l : D 2 interactions, D 1 tone also normally inhibits, via oppositional D I : D 2 interactions, the expression of atypical D2-stimulated behaviours such as jerking. Oppositional D I : D 2 interactions are evident using all of the classes of selective D 1 antagonist currently known, and appear to constitute another general mode of dopaminergic regulation. Dopamine D 1 receptors; Dopamine D 2 receptors; Dopamine D1/D 2 receptor interactions; Behaviour; Jerking; SCH 39166; NO 756; A-69024; BW 737C
1. Introduction The psychopharmacological and other effects of SCH 23390 have, since its introduction as the first selective D 1 dopamine (DA) receptor antagonist (Hyttel, 1983; Iorio et al., 1983), changed radically our perspectives on the functional roles of D A receptor subtypes in the regulation of psychomotor behaviour. It is now recognised at many levels of enquiry that D 1 and D 2 receptors often do not exert independent roles but rather interact fundamentally to determine the totality of DAergic function (Waddington and O'Boyle, 1987, 1989; Arnt, 1987; Clark and White, 1987; Waddington, 1989). Subsequently, in studies seeking to clarify further the role of D t : D 2 interactions in the regulation of behaviour, we have reported data consistent with two forms of such interaction: one cooperative/synergistic that appears to regulate typical DAmediated behaviours, the other oppositional that appears to regulate certain atypical DAergic responses
Correspondence to: J.L. Waddington, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland~ St. Stephen's Green, Dublin 2, Ireland.
(Murray and Waddington, 1989a); for example, SCH 23390 given prior to the selective D 2 agonist LY 163502 blocks typical sniffing and locomotor responses but releases episodes of atypical myoclonic jerking (Murray and Waddington, 1989b). However, the vast bulk of the above studies on D ~ : D 2 interactions has derived from the use of one selective D 1 antagonist, the benzazepine SCH 23390. T h e r e is clearly some considerable danger in elaborating new concepts and then seeking to refine them further all on the basis of essentially a single drug, but over this period no other class of D 1 antagonist has been available (Waddington and O'Boyle, 1989). Because of the therapeutic potential of such agents as antipsychotics (Waddington, 1988; Waddington and Daly, in press), several new, chemically distinct compounds have recently been identified: SCH 39166 (Chipkin et al., 1988), N O 756 (Andersen et al., 1988), A-69024 (Kerkman et al., 1989) and BW 737C (Riddall, 1992). It is therefore critical to establish the extent to which they might show properties similar to SCH 23390, particularly in the behavioural paradigm exemplified above which indicates a more complex profile of dual D I : D 2 interactions in the regulation of distinct elements of typical and atypical behaviour. Thus, to elabo-
252 rate further on the basis of such effects, we have utilised behavioural responses to the selective D 2 agonist R U 24213 (Euvrard et al., 1980; Pugh et al., 1985) and have studied the effects of SCH 39166, NO 756, A-69024 and BW 737C on such responses in comparison with SCH 23390 and the selective D 2 antagonist YM 09151 (Terai et al., 1989).
2. Materials and methods
2.1. Behavioural studies Young adult male Sprague-Dawley rats (125-365 g; Biolabs, B a l l i n a / U C D ) were used in all experiments. The rats were housed in groups of five per cage with food and water available ad libitum, and were maintained at 21 + I°C on 12/12 h (6:00 a.m. on; 6:00 p.m. off) light/dark schedule. On experimental days they were placed individually in perspex cages 52 x 39 x 18 cm and left undisturbed for a habituation period of 2.5 h. Behavioural assessments were carried out in a manner similar to that described previously (Murray and Waddington, 1989b; Daly and Waddington, in press). Immediately before and at intervals after injection of drug or vehicle, animals were assessed using a rapid time-sampling behavioural check list technique. For this procedure, each rat was observed individually for 5 s periods at 1 min intervals over 5 consecutive min, using an extended behavioural check list. This allowed the presence or absence of the following individual behaviours (occurring alone or in combination) to be determined in each 5 s period: stillness (St, motionless with no behaviour evident); sniffing (Sn); locomotion (L); rearing (R); grooming (Gr, of any form); intense grooming (a characteristic pattern of grooming of the face with the forepaws followed by vigorous grooming of the hind flank with the snout); vacuous chewing (not directed onto any physical material); chewing (Ch, directed onto any physical material); jerking (J, myoclonic movements of the limbs or whole body). When evident, jerks were quantified further using the following scale: 1 = small, 2 = medium; 3 = large, based on amplitude of movement and extent of bodily involvement (see Results). After assessment using the behavioural check list, animals were evaluated using a conventional 0 - 6 point stereotypy rating scale: 0 = asleep or inactive; 1 = episodes of normal activities; 2 = discontinuous activity with bursts of prominent sniffing or rearing; 3 = continuous stereotyped activity such as sniffing or rearing along a fixed path; 4 = stereotyped sniffing or rearing fixated in one location; 5 = stereotyped behaviour with bursts of licking or gnawing; 6 = continuous licking or gnawing. This cycle was repeated at 10 min intervals. Rats were used on
two occasions only, separated by a drug free interval of at least one week; on each occasion rats were randomly allocated to one of the various treatment groups. All assessments were made by an observer unaware of the treatment given to each animal.
2.2. Radioligand binding studies Using methods similar to those described previously (Murray and Waddington, 1989b; Daly and Waddington, in press), striata from similar male Sprague-Dawley rats were homogenised in 30 volumes of 50 mM Tris-HC1 buffer, pH 7.6 at 25°C, and centrifuged at 10000 x g at 4°C for 5 min. The pellet was twice resuspended, diluted and centrifuged as above. The membrane preparation was finally resuspended at 4 - 8 mg original wet weight/ml in Tris-HCl buffer containing: 120 mM NaC1, 5 mM KC1, 1 mM MgCI2, 2 mM CaC12, 0.2 mM Na2S205 (as antioxidant) and 1 0 / z M pargyline (as monoamine oxidase inhibitor). The binding of [3H]SCH 23390 (83 Ci/mmol, Amersham) to D 1 receptors was determined by incubating 0.5 ml of membrane suspension with 0.3 nM ligand and unlabelled drugs at 37°C for 20 min in a total volume of 1 ml. Specific binding was defined as that displaced by 100 nM piflutixol (Lundbeck), and typically represented 93% of total binding. Incubations were stopped by filtration through G F / B filters, followed by two 8 ml washes with ice-cold buffer. Radioactivity trapped on the filters was quantified by liquid scintillation spectroscopy after addition of 5 ml of liquiscint (Med labs) using a LKB 1214 Rackbeta counter with 51% counting efficiency for tritium. The binding of [3H]spiperone (15 Ci/mmol, Amersham) to D 2 receptors was determined using membranes prepared as above. Incubations contained 0.5 ml of membrane suspension with 0.18 nM ligand and unlabelled drugs in a total volume of 5 ml. Specific binding was defined as that displaced by 1 /zM domperidone (Janssen) and typically represented 82% of total binding. Incubation and filtration were as described above.
Z3. Drugs The following investigational drugs were used: R U 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine; Roussel-UCLAF, France); SCH 23390 (R7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-lH-3-benzazepine; Schering-Plough, USA); SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo[d]naphtho-[2,1b]-azepine; Schering-Plough, USA); NO 756 ([+]-8-chloro-5[2,3dihydrobenzofuran-7-yl] 3-methyl-2,3,4,5-tetrahydro1H-3-benzazepine; Novo, Denmark); A-69024 (112-
253
bromo-4,5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2methyl-l,2,3,4-tetrahydroisoquinoline; Abbott, USA); BW 737C (S-6-chloro-l-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline and its R-antipode BW 736C; Wellcome Foundation, UK); YM 09151 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide; Yamanouchi, Japan). RU 24213, SCH 23390 and BW 736C/737C were dissolved in distilled water; SCH 39166, NO 756 and A-69024 were dissolved in a minimum of acetic acid and made up to volume with distilled water; YM 09151 was dissolved in a minimum of dilute HC1 and made up to volume with distilled water. All drugs were injected subcutaneously into the flank in a volume of 2 ml/kg, with antagonists or respective vehicles given 30 min prior to agonist challenge.
2.4. Data analysis From the application of the behavioural check list, the total 'counts' for each individual behaviour was determined as the number of 5 s observation windows in which a given behaviour was evident, summed over a 1 h period, and expressed as means + S.E.; stereotypy scores were averaged over the 1 h period and expressed similarly. These data were then analysed using analysis of variance (ANOVA) or the Kruskal-Wallis non-parametric ANOVA, followed by Student's t-test or Mann-Whitney U-test, respectively. Data from radioligand displacement experiments were analysed by a computer-assisted non-linear iterative curve fitting procedure (Barlow, 1983). The resulting IC50 was converted to a K i value using the Cheng-Prusoff equation; K i = IC50/(1 + C / K D) where C is ligand concentration and K D is the apparent dissociation constant from saturation studies as described elsewhere (Daly and Waddington, in press).
3. Results
3.1. Behavioural studies When given alone, the selective D 2 agonist RU 24213 (0.5-15.0 mg/kg) reduced episodes of stillness and grooming, and induced dose-dependent increases in sniffing, locomotion and, occasionally, rearing; minimal chewing but no vacuous chewing, intense grooming or jerking was evident (table 1). Low scores on the stereotypy rating scale indicated that those behaviours stimulated were not being expressed in a classically stereotyped manner. On selecting as a challenge dose of RU 24213 that which resulted in the highest mean score on the stereotypy rating scale (15.0 mg/kg), its actions to decrease stillness and to induce sniffing and locomotion were readily and dose dependently blocked by pretreatment with the selective D 2 antagonist YM 09151 (0.005-0.5 mg/kg); the result was a quiescent animal, with no behaviour other than a trivial level of chewing emerging to fill this behavioural void. These typical sniffing and locomotor responses to RU 24213 were also readily reduced by the selective D~ antagonist SCH 23390 (0.01-1.0 mg/kg) but a quiescent state did not result. Rather, such pretreatment with SCH 23390 dose dependently released episodes of myoclonic jerking; these movements ranged from small but evident jerks of the head/upper body, through more generalised involvement of other body regions, to prominent jerking of the whole body with vigorous limb movements that could propel the animal upwards into the air from the floor of the cage (table 1, fig. 1). These jerks often had a brief 'activating' effect on animals in terms of the re-emergence of some episodes of sniffing over the first few seconds of each post-jerk period, and this phenomenon disrupted somewhat the dose dependency of the reduction in RU 24213-induced sniffing associated with SCH 23390 pretreatment; no such effect was evident in terms of RU 24213-induced locomotion,
TABLE 1 Induction of behaviours by RU 24213. Data are means ± S.E. of behavioural counts or stereotypy scores for n = 8 animals per group. Dose mg/kg
St
Sn
L
R
Gr
Ch
J
Stereotypy score
0.4±0.3
1.0± 0.6
2.3±0.7
1.3±0.6
0.0±0.0
0.4±0.1
0.8±0.5 2.8±0.9 a 9.5±2.2 a 8.1±1.5 a
1.4±0.9 2.9±0.8 4.0±1.3 1.9± 0.4
0.4±0.2 a 0.6±0.4 0.3±0.2 a 0.1±0.1 a
1.0±0.5 1.9± 0.6 1.9±0.5 0.6±0.2
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.2 1.5±0.1 a 1.6±0.1 a 1.9±0.1 a
~hic& -
17.5±2.6
9.8±2.4
RU24213 0.5 1.5 5.0 15.0
20.5±3.3 7.5 ±3.5 a 0.8±0.3 a 0.3±0.2 a
a p < 0.05 vs. vehicle
8.5±2.9 23.5±2.6 a 28.0±0.6 a 29.3±0.3 a
254 TABLE 2 Effects of YM 09151 and SCH 23390 on behavioural responses to RU 24213. Data are means± S.E. of behavioural counts or stereotypy scores for n = 8 animals per group. Drug
Dose mg/kg
St
RU24213 +YM09151
15.0 0.005 0.05 0.5
0.5±0.2 5.9±2.0 22.6±2.0 24.1±1.4
RU24213 +SCH23390
15.0 0.01 0.1 1.0
a
L a b b b
0.4±0.3 a 1.4±0.5 8.1±2.4 b 9.6±2.4 b
16.9±2.1 6.1±1.7 1.6±0.7 1.1±0.3
a b b b
12.8±1.9 a 7.1±2.1 3.0±2.3 b 0.8±0.5 b
R
Gr
Ch
Stereotypy score
1.3±0.6 1.8±0.9 0.3±0.3 0.1±0.1
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.3±0.3 1.6±0.6 1.1±0.3 b 0.1±0.1
1.9±0.1 1.2±0.2 0.2±0.1 0.1±0.1
3.1±0.8 a 4.4±1.2 a 2.1±0.9 1.3±0.6
0.1±0.1 0.0±0.0 0.1±0.1 0.0±0.0
0.5±0.4 1.3±0.8 1.1±0.4 0.4±0.3
1.6±0.1 a 1.5±0.1 0.9±0.2 b 0.7±0.2 b
a b b b
p < 0.05 vs. vehicle; b p < 0.05 vs. RU 24213 alone.
w h i c h w a s e s s e n t i a l l y a b o l i s h e d by S C H 23390 ( t a b l e 2, fig. 1). E a c h o f t h e n e w s e l e c t i v e D , a n t a g o n i s t s S C H 39166 ( 0 . 1 - 1 0 . 0 m g / k g ) , N O 756 ( 0 . 0 1 - 1 . 0 m g / k g ) , A - 6 9 0 2 4 (1.0-25.0 mg/kg) and BW 737C (0.2-5.0 mg/kg) c a u s e d r e d u c t i o n s in R U 2 4 2 1 3 - i n d u c e d s n i f f i n g a n d l o c o m o t i o n w h i l e r e l e a s i n g m y o c l o n i c j e r k i n g . I n all i n s t a n c e s t h e r e d u c t i o n in l o c o m o t i o n w a s d o s e - d e p e n d e n t , w h i l e t h a t f o r s n i f f i n g w a s a g a i n d i s r u p t e d by b r i e f a c t i v a t i o n in t h e i m m e d i a t e p o s t - j e r k p e r i o d s , as d e t a i l e d a b o v e ; this p h e n o m e n o n was particularly p r o m i n e n t f o r S C H 39166 a n d B W 737C. A t t h e d o s e s u s e d , S C H 39166 a n d B W 7 3 7 C r e l e a s e d t h e g r e a t e s t n u m b e r o f j e r k s w h i l e A - 6 9 0 2 4 w a s less e f f e c t i v e ; N O 756 s h o w e d an i n t e r m e d i a t e l e v e l o f activity, s i m i l a r to t h a t o f S C H 23390, T h e a c t i o n s o f B W 7 3 7 C t o r e d u c e R U 2 4 2 1 3 - i n d u c e d s n i f f i n g a n d l o c o m o t i o n a n d to re-
lease episodes of jerking showed complete enantioselectivity, its R - a n t i p o d e B W 7 3 6 C (5.0 m g / k g ) b e i n g e n t i r e l y w i t h o u t e f f e c t ( t a b l e 3, fig. 2). The nature of the dose-dependent release of jerking to R U 24213 by e a c h o f t h e five s e l e c t i v e D 1 a n t a g o nists was e x a m i n e d f u r t h e r . C o m p a r i s o n o f s c o r e s for t h o s e j e r k s m a n i f e s t e d at e a c h d o s e o f t h e D 1 a n t a g o nists i n d i c a t e d t h a t i n c r e a s e s in b e h a v i o u r a l c o u n t s w e r e n o t a c c o m p a n i e d by any g e n e r a l i n c r e a s e in severity o f j e r k i n g m o v e m e n t s ( o v e r a l l m e a n s c o r e 1.9 + 0.1; r a n g e 1 . 4 - 2 . 5 ) ; i n d e e d , t h e m o r e f r e q u e n t t h e jerks, t h e less s e v e r e t h e y t e n d e d to be.
3.2. Radioligand binding studies B o t h S C H 39166 a n d N O 756 d e m o n s t r a t e d h i g h affinity a n d s e l e c t i v i t y for D 1 r e c e p t o r s , c o m p a r a b l e to
TABLE 3 Effects of SCH 39166, NO 756, A-69024, BW 736C and BW 737C on behavioural responses to RU 24213. Data are means± S.E. of behavioural counts or stereotypy scores for n = 6-16 animals per group. Drug
Dose mg/kg
St
RU24213 +SCH39166
15.0 0.1 1.0 10.0
1,0±0.6 13.1±2.7 10.1±2.7 8.3±2.5
a b b b
4.9±0.7 0.6±0.5 0.6±0.3 0.8±0.5
RU24213 +NO756
15.0 0.01 0.1 1.0
0.6±0.3 3.3±1.8 11.5±2.7 12.4±1.8
a b b b
11.4±1.6 a 9.3±2.9 2.0±0.8 ~ 0.4±0.2 b
RU24213 +A-69024
15.0 1.0 5.0 25.0
0.9±0.3 a 3.3±1.3 10.5±2.6 ~ 14.8±2.0 b
7.5±1.6 a 5.8±1.5 2.1±1.1 b 0.1±0.1 b
RU24213 +BW 736C +BW 737C
15.0 5.0 0.2 1.0 5.0
0.3±0.1 0.4±0.2 10.3±2.8 9.3±1.5 11.0±0.3
a
L
a a ~ b b
p < 0.05 vs. vehicle; b p < 0.05 vs. RU 24213 alone.
11.5±2.0 11.4±3.5 5.1±2.6 2.9±1.2 1.5±0.9
a b b b
a a b b
R
Gr
Ch
Stereotypy score
0.5±0.3 0.6±0.4 0.6±0.4 1.1±0.5
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
1.0±0.6 0.1±0.1 0.1±0.1 0.0±0.0
1.6±0.1 0.7±0.2 0.7±0.1 1.0±0.1
1.9±0.5 a 4.3±1.3 a 0.4±0.2 1.4±0.4 a
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.3 0.5±0.2 0.4±0.2 0.3±0.2
1.7±0.2 a 1.5±0.2 0.7±0.1 b 0.7±0.1 b
0.9±0.4 0.8±0.5 0.5±0.4 1.4±0.6
0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
0.5±0.2 0.5±0.3 0.3±0.2 0.3±0.2
1.7±0.1 a 1.0±0.2 0.7±0.1 b 0.5±0.5 b
1.0±0.2 1.5±0.4 1.0±0.5 1.9±0.9 0.4±0.3
0.0±0.0 0.1±0.1 0.0±0.0 0.0±0.0 0.0±0.0
0.1±0.1 0.0±0.0 0.0±0.0 0.0±0.0 0.0±0.0
1.8±0.1 1.9±0.1 0.7±0.2 0.8±0.1 0.6±0.1
a b b b
a a b b b
255
"t
YM 09151
Sniffing
II
il
11,,
oli,.
2O
10
0
TABLE 4
SCH 23390
Jerking
15
10
t
5 0
m
__
RU V 15 15 15 15 YM V V .005 .05 .5
i
--'r--
|i
Displacement of [3H]SCH 23390 and of [3H]spiperone from striatal D l and D 2 receptors, respectively, by investigatory agents. Values are geometric means of at least three independent determinations, each performed in duplicate. Drug
K i (nM)
D 1/D~
[3H]SCH 23390 (D l)
[ 3H]spiperone (D 2)
16 634 6884 0.18 0.72 0.18 24.5 0.31 895
244 0.23 846 998 782 1343 36.5 2410
RU 24213 YM 09151 SCH 23390 SCH 39166 NO 756 A-69024 BW 737C BW 736C
68 29930 0.0002 0.0007 0.0002 0.018 0.008 0.37
RU V 15 15 15 15 SCHV V .01 .1 1.0
Fig. 1. Behavioural counts for sniffing and jerking responses to RU 24213 (RU; 15.0 mg/kg) after pretreatment with vehicle (V), YM 09151 (YM; 0.005-0.5 mg/kg) or SCH 23390 (SCH; 0.01-1.0 mg/kg). Data are means_+S.E, of n = 8 animals per group, a p < 0.05 vs. vehicle; * P < 0.05 vs. RU 24213 alone.
SCH 23390. A-69024 showed the lowest D 1 receptor affinity and selectivity of the new antagonists examined, while BW 737C showed high affinity but somewhat reduced selectivity for D1 receptors; these propSCH 39166
erties of BW 737C were characterised by essentially complete enantioselectivity, its R-antipode BW 736C showing negligible D i receptor affinity and selectivity (table 4). The rank order of affinity for D 1 receptors was N O 756 = SCH 23390 -- BW 737C -- SCH 39166 >> A-69024, while the rank order of selectivity for D 1 vs. D 2 receptors was N O 756 = SCH 2 3 3 9 0 - - S C H 39166 > BW 737C > A-69024. In comparative studies, the reference compounds R U 24213 and YM 09151 were confirmed to show selective affinity for D 2 receptors.
NO 756
A-69024
BW 736/7C
Sniffing
linn
:t10 ~ i l l l o
""
Jerking
.
RU V SCH V
.
.
.
_
15 15 15 15
RU
V
NO V
.1 1.0 10
V
15
15 15 15
V .01 .1 1.0
_
i
.
RU
V
15 15 15 15
A
V
V
.
1
_
5
25
_
_
RU
V 15
BW
V
V
15 15 15 15 5
.2
1
5
R S S S
Fig. 2. Behavioural counts for sniffing and jerking responses to RU 24213 (RU; 15.0 mg/kg) after pretreatment with vehicle (V), SCH 39166 (SCH; 0.1-10.0 mg/kg), NO 756 (NO; 0.01-1.0 mg/kg), A-69024 (A; 1.0-25.0 mg/kg), the R-enantiomer BW 736C (BW, R; 5.0 mg/kg) or its S-antipode BW 737C (BW, S; 0.2-5.0 mg/kg). Data are means+S.E, of n = 6-16 animals per group, a p < 0.05 vs. vehicle; * P < 0.05 vs. RU 24213 alone.
256 4. Discussion
While the concept of cooperative/synergistic D~ : D 2 interactions in the regulation of typical DAergic behaviours has received considerable attention (Waddington and O'Boyle, 1987, 1989; Arnt, 1987; Clark and White, 1987; Waddington, 1989), it derives essentially from studies with the first selective D~ antagonist, the benzazepine SCH 23390, and its partial agonist congener SK&F 38393. Of greater concern here is the proposal that such a schema requires modification to accommodate evidence for other, atypical behaviours appearing to be regulated by distinct, oppositional D~ : D 2 interactions (Murray and Waddington, 1989a,b). Were similar results to be obtained using several new, chemically distinct selective D~ antagonists that have become available only recently, this would constitute important evidence for the generality of such a proposal and could provide much needed clues as to the nature of such processes. We find that each of a series of novel selective D~ antagonists, the benzonaphthazepine SCH 39166 (Chipkin et al., 1988), the benzofuran NO 756 (Andersen et al., 1988) and the tetrahydroisoquinolines A69024 (Kerkrnan et al., 1989) and BW 737C (Riddall, 1992), shares with SCH 23390 the following properties: (i) antagonism of typical sniffing and locomotor behaviour induced by the selective D e agonist RU 24213, via reduction of D 1 tone that is normally 'permissive' or 'enabling' for the expression of such typical D 2stimulated behaviours in accordance with cooperative D 1:D 2 interactions (Waddington and O'Boyle, 1989; Waddington, 1989); (ii) release of atypical myoclonic jerking behaviour in response to RU 24213, apparently via reduction of D1 tone that would normally inhibit the expression of such atypical Dz-stimulated behaviour in accordance with postulated oppositional D 1: D 2 interactions (Murray and Waddington, 1989a,b). Jerking was never seen spontaneously and was an extremely rare response to RU 24213 given alone or after pretreatment with the selective D 2 antagonist YM 09151. Such D 2 antagonist pretreatment acted only to block the typical sniffing and locomotor responses to RU 24213, indicating that jerking was not released by the D~ antagonists through simple attenuation of competing behaviours. The complete enantioselectivity of this effect, seen robustly with the S-enantiomer BW 737C but not at all with its R-antipode BW 736C, paralleled their enantioselective blockade of D~ but not D 2 receptors. SCH 39166 and BW 737C were the most effective releasers of jerking, and these are the two 'cleanest' of the new selective D~ antagonists; for example, they show less affinity for 5-hydroxytryptamine 2 receptors than do SCH 23390 and NO 756 (Chipkin et al., 1988; Riddall, 1992; Andersen et al., 1988), which were less effective releasers of jerking.
A-69024 showed both the lowest affinity for D~ receptors and the lowest D J D 2 selectivity ratio (see also Kerkman et al., 1989), and was the least effective releaser of jerking among the compounds examined. These data indicate an essential role for concurrent suppression of D~ receptor-mediated function in the genesis of D 2 agonist-induced jerking. The nature of this jerking response is not well understood. It seems to have been first described and so named by Grabowska-And6n and And6n (1983) as a response to the D 2 'autoreceptor' agonist B-HT 920 and to a lesser extent to apomorphine after pretreatment with reserpine. Subsequently, a similar response to such agents was noted following pretreatment with SCH 23390 and its close homologue SK& F 83566, and the possibility of a basis in D 2 stimulation during concurrent D~ blockade was considered (Waddington et al., 1986; Grabowska-And6n and And6n, 1987; Murray and Waddington, 1989b). Phenomenologically, perhaps the closest human parallel is that of sudden bodily jerks sometimes experienced on falling asleep (Oswald, 1959); D~ antagonism can induce sedation and increase sleep duration (Trampus and Ongini, 1990), hence D 2 activity under these conditions might provoke such phenomena. At the human level there is little evidence that this behaviour is related to any epileptic state (Oswald, 1959), and recent animal studies indicate D~ antagonism and D 2 agonism rather act to raise seizure threshold in a variety of convulsive paradigms (A1-Tajir et al., 1990; Barone et al., 1991). Thus, jerking might be best considered at this stage to be an episodic, atypical motor behaviour rather than a reflection of any epileptogenic process. If the behavioural data reported here are to be used to buttress and extend the concept of two directions of D~ :O 2 interaction, are distinct profiles of such interaction apparent at other levels of examination? The well-known cooperative/synergistic D 1 : D 2 interactions that regulate typical DAergic behaviours (Waddington and O'Boyle, 1989; Waddington, 1989) are readily paralleled by very similar profiles of D I : D 2 interaction in the regulation of striatal, accumbal and pallidal electrophysiology (Waiters et al., 1987; Wachtel et al., 1989); furthermore, cooperative/synergistic D~ : O 2 interactions at the neurochemical level have recently been described (Bertorello et al., 1990; Piomelli et al., 1991). Oppositional D I : D 2 interactions, which appear to regulate certain atypical DAergic behaviours such as jerking, may have a ready parallel in the opposing roles of D~ and D 2 receptors in regulating the activity of striatal adenylate cyclase (Stool and Kebabian, 1981; Onali et al., 1985), but it is only more recently that comparable electrophysiological interactions have been reported, in the ventral pallidum/substantia innominata (Maslowski and Napier, 1991); recent studies at other levels of function also indicate
257
oppositional D t :D 2 interactions, at least in the striaturn (Altar et al., 1990; Damsma et al., 1990). However, the site(s) involved in the genesis of jerking behaviour remain poorly defined, though it appears to constitute a potentially useful model for such particular DAergic mechanisms. The present data indicate two directions of D~:Dz interaction, cooperative in the regulation of typical DA-mediated behaviours and oppositional in the regulation of certain atypical DA-mediated behaviours such as jerking, to be a finding generic to all of the classes of selective Dt antagonist currently available; there appear to be distinct putative correlates of each of these two forms of D1:D 2 interaction at both the electrophysiological and neurochemical levels. What is less clear is whether DI and D2 receptors involved in cooperative/synergistic interactions are homogeneous with those involved in their oppositional counterparts. It remains possible that any such differences might represent functional distinctions between members of the families of 'Dr-like' (DIA, Dm and D 5) and 'D2-1ike' (D2L, D2s, D 3 and D 4) DA receptor subtypes identified recently in molecular biological studies; however, clarification of this issue will have to await the identification of compounds better able to discriminate between the individual members of each family (Waddington, 1991). Irrespective of this, D~:D 2 interactions do not appear to act in a uniformly cooperative/synergistic manner; their oppositional counterparts appear to act more generally than has been recognised previously, and will need to be taken into account when seeking to explain DAergic phenomena.
Acknowledgements This work was supported by the Wellcome Trust. We thank Abbott, Novo, Roussel, Schering, Wellcome Foundation and Yamanouchi for kindly making compounds available to us.
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