Dopamine D1- and D2-receptor interaction in turning behaviour induced by dopamine agonists in 6-hydroxydopamine-lesioned rats

~,'etoost u'n¢ e Lt'tttr~ 88 (1988) 69 74 Flse~ter ScientificPubhshers Ireland Ltd

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Dopamine D 1- and D2-receptor interaction in turning behaviour induced by dopamine agonists m 6-hydroxydopamine-lesioned rats Gorll Karlsson, Anne-Llse Jaton and Jean-Marie Vlgouret Pre¢ hm~al Reww~ h 5ando: Lid

Ba~el (~l~tlzerland)

(Received 15 October 1987 Revised ~erslon received 26 Januar~ 1988 Accepted26 Januar~ 1988) Act llords

Dopamlnt.(DA) receptor (ircllng behavior Dopamme agonlst Dopamme antagonl',t

Tht. selectl,,Cdopamlnc Dz-antagonlst sulplrlde potentiated contralateral circling beha,dour induct.d b', the D~-agomst (_Y 208-243 in rats with unilateral lesions of substantla nlgra, but reduced the ~lTfLctsol the selecnxe D,-agonlst bromocrlptlne Similarly, the Dr-antagonist SCH 2"~90 tended to Increase the eltects of bromocrlptlne but markedly inhibited CY 208-243 induced turning The mixed D~ D:-antagomst fluphenazlnc was eflectl,,e in reducing circling beha~lour Induced by either agonlst v,hereas plmo,'ldL[D~ D) Inhibited onl', the acnons ol bromocrlptlne These results indicate that the actions of ( "~ 208-24t and bromocnptm~, are mediated via distinct but interacting receptor subtypes

D o p a m m e (DA) receptors in the brain have been classified as Di- a n d D2-subtypes a c c o r d m g to biochemical studies [6, 12] ActlvaUon of Di-receptors leads to an increase m adenylate cyclase activity [12] The second messenger system l o t the D:receptors is yet unclear However, the m h t b m o n of adenylate eyclase appears to be a n i m p o r t a n t effeetor m e c h a n i s m for the D2-receptors [21] The behavloural and motor effects of D A in n o r m a l a m m a l s were previously beheved to be primarily mediated by the D : - r e c e p t o r [6, 19] M o r e recently however, selectwe Dl-receptor s t i m u l a t i o n has been shown to lead to exaggerated g r o o m i n g b e h a v t o u r a n d n o n , t e r e o t y p e d stuffing [15, 16], suggestmg a direct f u n c t i o n a l role for Dwreceptor~ in m o t o r c o n t r o l There is also ewdence that D i - r e c e p t o r s t i m u l a t i o n famhtates D : - a g o rest-reduced behavloural changes [4 5] The a m m a l model most c o m m o n l y used to mvest~gate the central effects of DA on m o t o r f u n c n o n is t u r n i n g b e h a v m u r in rats with unilateral 6 - h y d r o x y d o p a m m e ( 6 - O H D A ) m d u c e d lesions of the n l g r o s t n a t a l p a t h w a y In this model, both D I- and De-agomsts produce c o n t r a l a t e r a l r o t a t i o n a l b e h a v l o u r [3, 7 8], p r e s u m a b l y by actmg on s t n a t a l D A - r e c e p t o r s rendered s u p e r s e n s m v e by the lesmn [22] These recep-

(~otr~ ~pomh,mt A L Jaton Precllnlcal Research Sandoz ktd CH-4002 Basle SwltTerland

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tors were thought to be stimulated or blocked mdependentl~ by their respective ago nlsts and antagonists [2] Recent reports, however, suggest that an interaction between these two receptor bubtypes ma~, occur even after chemical dener,~atmn [17 23] We have investigated the posslblhty ol such a receptor interaction by studying the effects of the selective DA receptor antagomsts SCH 23390 (DI) and sulplrlde (D2), and the mixed Dj/D2-receptor antagomsts fluphenazlne and plmozlde [10] on responses to CY 208-243, a new DI-agonlst [14] and the D2-agonlst bromocrlptlne [11 13] Male O F A rats (140 160 g) were lesioned at the level of the substantl,l nlgra with a unilateral injection of 6 - O H D A HC1 (Janssen) (8/lg of free base in 4 i;1 of saline containing 0 2% ascorblc acid, injected over 12 ram) The stereotaxlc coordinates were 4 2 mm posterior and 1 0 m m lateral to the bregma and 7 5 mm ventral measured from the dura The Incisor bar was adjusted to 2 4 m m below the mteraural line Four weeks post-operatively, the animals were challenged with apomorphlne HCI (Sandoz) 0 25 mg/kg s c , only those rats responding with at least 460 contralareval turns were used tor subsequent drug testing Since the sensitivity to apomorphlne varied from ammal to animal according to the extent of denervatlon, the response to a given test drug (recorded on an automatic rotometer at 2 rain intervals per 7 h) was corrected by multiplying the number of turns by the mean response to apomorphlne prewously recorded m 100 rats, i e 560 turns, divided by the response to apomorphlne in that animal All antagomsts were injected I h before administration of 3 mg/kg p o CY 208-243 (Sandoz) Because of the long latency of bromocnptlne Induced contralateral turnlng sulplrlde (Delagrange) and SCH 23390 (Scherlng) were administered 15 rain before 20 mg/kg p o bromocrlptlne (Sandoz), whereas the long-acting antagomsts fluphenazme (Squibb), and plmozlde (Janssen) were admlmstered 1 h prior to the agonlst The antagonists were given i p at the following doses 30 mg/kg sulplrlde, 0 5 mg/kg SCH 23390, 1 mg/kg plmozlde and 1 mg/kg fluphenazme All drugs except SCH 23390 were dissolved m a few drops of lactic acid 1% and made up to volume adjusted to pH = 4- 5 SCH 23390 was dissolved in a drop of HCI 1 N and ethanol and made up to volume at adjusted pH = 4-5 Cross-over studies were performed in all cases During the first week of experiments, groups of 6-12 ammals were treated with either CY 208-243 or b r o m o c n p t m e alone Two weeks later these animals received the same agonlst as before together with one of the antagomsts Student t-test for paired data was employed for statistical analysis of the results Oral administration of CY 208-243 mduced long-lasting contralateral turmng after a latency of only 10 m m (Fig 1) B r o m o c n p t m e also reduced long-lasting contralateral turning (Fig 1), but the onset of acnon was much slower (latency = 60 rain) The effect of CY 208-243 was markedly inhibited (91 0_+ 7 7%) by the Dj-selectlve antagonist SCH 23390 and to a lesser extent (49 7 4- 5 8%) by the mixed Di/D2-antagomst fluphenazme (Fig 2) By contrast, selective D2-receptor blockade by sulpmde reduced a strong potentmtlon of the response (89 1 + 10 7%) (Fig 2) The mixed DI, D2-antagomst plmozlde increased CY 208 243-mduced turning by 20 0 ± 37 5% but this value did not reach statistical significance (Fig 2)

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Fig 1 ( ontralaleral turning (turns'ram) reduced by CY 208-243 ( n = 6 ) and bromocrlptme (n =6) in rats v, lth unilateral 6-OHDA-lnduced legions of the substantla mgra Fach ~alue is the m e a n + S F M The ~ehlcle mduecd a neghglble number ol turns (20 0 ± 5 5 m 7 h n = 6 data not sho~n)

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F~g 2 Percentage change of CY 208-24~,-lndueed contralateral turning m rats v, lth umlateral 6-()HDAreduced lesions o[ the substantla mgra b'~ SCH 23390 (0 5 mg,'kg 1 p n - 6 ) sulplNde 1~0 mg kg 1 p n = 1 2 ) fluphcnazmc(l m g k g l p n = 6 ) and plmozlde (l m g / k g l p n 6) * P < 0 0 5 **P<'O(I1 u~mpared ~mth the effect of CY 208-243 alone

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Fig 3 Percentage change of bromocnptmc-mduced contralateral turning m rats with unilateral 6-OHDAreduced lesmns of the substanna mgra by SCH 23390 (0 5 mg/kg i p n = 6), sulpmde (30 mg/kg ~ p , n = 6) fluphenazme (1 mg/kg i p , n = 6) and plmomde ( 1 mg/kg i p n = 7) * P < 0 05, * * P < 0 01 compared with the effect of bromocrzptme alone

Fig 3 shows that turning behavlour induced by bromocrtptine was markedly lnhlNted by the mixed Dt/D2-antagomsts fluphenazme (899+39%) and plmozlde (860+8 5%), whereas the D2-antagomst sulpmde was somewhat less effectwe (67 8 + 7 8%) Selective Drblockade with SCH 23390 enhanced the effect of bromocriptme by 41 0 + 23 7% However, this value did not reach statistical slgmficance The selectwe Dl-agomst CY 208-243 and the D2-agonlst bromocnptlne both reduce contralateral rotations m animals with stnatal receptor supersensmvlty induced by lesmnlng of the nlgrostnatal pathway The effects of the two compounds could be rea&ly dlstmgutshed from each other using appropriate antagonists such as SCH 23390 (D0 and sulplrlde (D2) These findings support earher studies that D1- and D2-receptors can independently medmte behawoural effects m a m m a l s after 6OHDA-mduced lesmns [2] The fact that sulpmde was less effective m antagomzmg the effect of bromocriptme than the mixed antagonists fluphenazme and plmoz~de was probably due to its relatively weak central actlwty [1] Fluphenazme was more effective m antagonizing the rotatmns reduced by bromocnptme than those by CY 208-243, whereas plmoz~de inhlNted only the actmns of bromocrlptlne This difference may reflect the preferential affinity of these two latter antagonists, particularly plmozlde, for the D2 receptor [10] Surpnsmgly, sulpmde markedly increased the number of turns reduced by CY 208-243 Potentlatmn of Drreceptor-mediated effects after selective D2-receptor blockade have also been reported for the Dj-agomst SKF 38393 in a behawoural study in naive rats [18] and in the in v i t r o adenylate cyclase assay [20] In analogy to the interaction observed between CY 208-243 and sulplnde, turning reduced by bromocnptme tended to be potentmted by SCH 23390 Contrasting results can be found m the hterature concerning mteractmns between

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the D A receptor subtypes Behavtoural studies with normosensmve d o p a m m e receptors have provided ev,tdence for a pos,ttlve ,interact,ton between Dr- and D~-receptor st~mulat,ton [4, 5] More recently, s,tm,tlar observat,tons were made in 6 - O H D A les~oned rats It was reported that concurrent D~- and D2-receptor stimulation w~th SKF 38393 and bromocrlptme respect,tvely result ,in a synerg,tstlc effect on substantla mgra pars ret,tculata neuronal act~wty [24] and on rotat,tonal behav,tour [17] Threshold dose of bromocrtpt,tne (10 mg/kg p o ) potent,rated the act,ton of CY 208-243 when a threshold dose (0 3 mg/kg p o ) was adm,tmstered (results not sho~n) However th~s actmn appears to be add,ttlve rather than synerg,tst~c, since no potenuauon was obtained with subthreshold doses (mact,tve alone) of the two DA agomsts Other m~ est|gators have found that turmng ,induced by the preferential D:-agonlst pergohde ~s mcreased when the ammals are pretreated w~th SCH 23390 [9] Th~s ~s m agreement w~th our findings w,tth bromocr,tptme Our hndmgs suggest that DI- and D:-agomsts exert the,it act,tons on separate receptor subtypes m les,toned ammals However, select,tve ,tnh,tb,tt,ton of one receptor subtype seems to ~e,mforce the actmns of a selective agomst o f the other subtype Taking into account only dopam,tnerg,tc mechamsms, these results suggest a phys~olog,tcal mteractmn between D~- and D:-receptors, each receptor mediating a negative regulator~ influence on responses evoked by st,tmulatlon of the other

I Arn,t J Pharmacological specificity ol conditioned avoidance response inhibition in ra,ts mhlbl,tlon b', ncuroleptlcS and correlanon (o dopamlne receptor blockade Acta Pharmacol 51 ( 19821 z;21 ~29 2 Arnt J and H~,ttel J Differential inhibition by dopamlnc D~ and D: an,tagonlsts ol circling bcha``lour reduced b~ dopamlnc agonlsts in rats with unilateral 6-h``droxydopamlnc lesions Eur 1 Pharmaeol 102 (19841 ~,49 354 :, Arnt J and H~,ttel J Differential involvement o1 dopamlne D~ and D, receptors in the circling bcha~iour induced h,< apomorphlne SKF ~839~, pergohde and L~ 171555 m 6-h,,droxvdopamme-lesloned rats Ps~chopharmacologv 85 119851 346 :,52 4 Arlu J H ) t t d J and Perregaard, J Dopammc D~ receptor agomsts eomblned ~Jth .the sdeLmc D, agomst qulnplrolc laclhtate the expression ot oral stereotyped behavlour in rats Eur J Pharm,leol 1:,1,11987) 1:,7 145 5 Braun A R and ( h a s e T N Obligatory Dt,'D, rccep,tor lnterachon In the generation ol dopalnlnc agomst relalcd behawors Eur J Pharmacol 131 (1986) 301 q06 6 ( recse I Slble,~ D R Hambhn M W and Left S E The classlfica,tlon o1 dopamlne r~.cep,tors ida ,tlonshlp to radmhgand binding Annu Re,, Neuroscl 6 (1983) 43 71 7 Herrcra-Marschwlt,' M Hyttel J and Ungerstedt U The dopamlnc Dj an,tagonls,t S(_H 2~,:,91) inhibits apomorphlne but not pergohde induced rotation Acta Phvslol Scand 122 11984) 427 428 8 tferrcra-Mar,,chwlt/ M and Ung~.rstcd,t U Ewdcnce .that apomorphlne and pergohde Induct. rotation in rat', b'y different action on D Land D, receptor sl,tes Eur J Pharmacol 98 (1984) 165 176 9 llcrrt.ra-Marschv, ltZ M and Ungcrstedt U Effect ol the dopamlnc Dt an,tagoms,t SC H 2q~911 on rot ttlonal behav~our induced by apomorphlne and pergohde m 6-h``drox~-dopamme dener~ated rats Eur ) Pharmacol 109 11985) M9 q54 10 H~ttcl J SCtt2~390 thefirstselectl``edopammeD~antagonlst, Fur J Pharmacol 91 1198:,) 1"~:, 1"~4 I1 Iohnson A M Locw D M and Vlgouret J M Stlmulan,t properties ol bromo~.nptnac on central dopammc receptors in comparison 'to apomorphlne, ( + )-amphetamine and l -DOPA Br J Pharlnacol 56(1976)59 68 12 kebablan J W and Calnc D B Multiple receptors lor dopamln~. Nature ( L o n d ) 277 (1979) 9:, 96

~4 I z; Markstem R Nt, urochemlcdl eflcct~ ol some ergot derl,~dtlVeS d bdslS [or their dntlparkmson at.tlon. J Neural Transm 51 (1981) 39 59 14 Markstem R , Seller M P ~¢lgourct, J M Urv~yler, S Enz A and Dixon K Pharmacological properties ot C'Y 208-24~; a novel I)~ agomst Proceedings of the 6th International (_,ltecholammc S y m p o s m m Jerusalem June 14-19 (1987), m press 15 Molto), A G and Waddlngton J I Dopamlnerglc behavlour stereospeclfically promoted by the I), agonlst R-SK&F 38393 and sclectwel) blocked by the Di antagonist SCH 23390 Ps,cchopharmacolog), 82 (1984) 409 410 16 Mollov A G and W a d d m g t o n J k Smmng, rearing and locomotor responses to tht Dt dopamlne ,lgomsl R-SK&F 38993 and to a p o m o r p h m e differential interactions with the selectl~t. Dt and I) antagomsts SCH 23"~90 and metoclopramlde Eur J P h a r m a c o l , 108 (1985) 305 ~;08 17 Robertson G S and Robertson H A Synergistic effects of D~ and Dz dopamlne agomsts on turning behavlour m rats Brain R e s , 384 (1986) 387 390 18 Rosengarten H Schweltzer J W and Frledhoff A J Induction o| oral dvskmeslas in nalxe rats b) D~ stlmulatmn [tfe ScJ ~ (198~;) 2479 2482 19 Sceman P Brain dopalmne receptors, Pharmacol R e v , 32 (1981) 229 313 20 Stoof J C and Kebabmn I W Opposing roles for D~ and D~ dopamlne receptors m efllux of cyclic A M P from rat n e o s t n a t u m Nature ( L o n d ) 294 ( 1981 ) 366-368 21 Stool J ( and Kebablan J W Two dopamlne receptors biochemistry, physiology and pharmacolog~ Lde Scl , 35 (1984) 2281 2296 22 Ungt.rstedt U Postsynaptlt. supcrsensmv~ty after 6-hydroxydopamme induced degeneratmn ot the mgro-stnatal dop,unme s,~stem tn the rat brain Acta Physml S c a n d , 82 Suppl 367 (1971) 69 78 2~; Wclt.k B G and Walters I R Fffe~.ts of D~ and D, dopamtne receptor stimulation on the acttwt,, ol substantm mgra pars retleulata neurons m 6-hvdroxydopamlne lesioned rats D~,D~ t.oactl~atlon reduces potentiated responses Brain Research 405 (1987) 234 246 24 Welck B G and Waiters J R D~ dopamlne receptor stimulation potentiates neurophyslologlcat elleers of bromocnptlne m rats with lesions of the mgrostrlalal d o p a m m e pathwa}, Neuropharmacologv 26 (1987) 641 644