Blockade of apomorphine-induced aggression by morphine or neuroleptics: Differential alteration by antimuscarinics and naloxone

Pharmacology Bzochemistry & Behavior, Vol. 4, pp. 6 3 9 - 6 4 2 Copyright © 1976 by ANKHO International Inc All rights of reproduction m any form reserved Printed m the U S A

Blockade of Apomorphine-lnduced Aggressi by Morphine or Neuroleptics: Differentia Alteration by Antimuscarinics and Naloxo GERALD GIANUTSOS l AND HARBANS LAL

Department o f Pharmacology and Toxicology, Umverst O, o f R h o d e Island Kingston R I 02881 ( R e c e , v e d 15 D e c e m b e r 1 9 7 5 ) GIANUTSOS, G AND H. LAL Blockade of apomorphme-induced aggresston by morphine or neurolepttcs dtfferenttal alteration by antlmuscarmws and naloxone PHARMAC BIOCHEM BEHAV 4(6) 639-642, 1976 - Both morphine and the neuroleptlcs, halopendol and oxyperomlde, dose-dependently reduce the aggression m rats produced by 20 mg/kg of apomorphine, a dopamlne receptor stimulant The narcotic antagomst, naloxone, prevents this effect of morphine but not the effect of neuroleptlcs Dexetlm~de, a centrally acting antlmuscanmc drug, antagonizes the reduction m aggression produced by the neuroleptlcs, but does not affect morphine's action The chohnergxc agonlst, pllocarpme, enhances th~s action of oxyperom~de These results suggest that a cholanerg~c component contributes to the ant~-agresslon action of neuroleptlcs and demonstrates a difference m the mechanism of action between neuroleptlcs and morphine Apomorphine

Morphine

Haloperldol

Oxyperomlde

H A L O P E R I D O L a n d m o r p h i n e have in c o m m o n a n u m b e r o f b e h a v i o r a l a n d n e u r o c h e m i c a l effects w h i c h are r e l a t e d to t h e d o p a m m e r g i c s y s t e m s in the CNS [9,11 ] H o w e v e r , t h e lack o f a d d i c t i o n habd~ty o f the n e u r o l e p t l c s i n d i c a t e s t h a t t h e r e is also a m a j o r d i f f e r e n c e in the a c t i o n s o f these drugs This w o u l d suggest t h a t t h e 2 drugs have dissimilar m e c h a n i s m s , w h i c h m a y reflect d i f f e r e n t a c t i o n s o n the manner that dopamine interacts with other neurotransm i t t e r s in t h e b r a i n It has b e e n d e m o n s t r a t e d t h a t t h e n a r c o t i c a n t a g o m s t , n a l o x o n e , reverses the a c t i o n of m o r p h i n e in p r o d u c i n g c a t a l e p s y [8] a n d i n h i b i t i n g b r a i n s e l f - s t i m u l a t i o n [ 19], b u t t h e similar a c t i o n s o f n e u r o l e p t l c s are u n a f f e c t e d b y n a l o x o n e Conversely, these effects o f h a l o p e r i d o l are a n t a g o n i z e d b y a n t i c h o h n e r g i c s w h i c h do n o t alter the actions of morphine [3,20] These earlier studies have dealt w i t h simple b e h a v i o r a l effects o f these c o m p o u n d s . In the p r e s e n t study, we d e c i d e d to investigate the ability of n e u r o l e p t l c s a n d m o r p h i n e to a n t a g o n i z e t h e a c t i o n o f a dopamlnerg~c agonlst, a p o m o r p h i n e [ 1 , 1 3 ] , m o r d e r to e x a m i n e t h e i r d o p a m m e b l o c k i n g action. A n y d i f f e r e n c e s in t h e a b l h t y o f s u b s t a n c e s to o p p o s e this a c t i o n o f m o r p h i n e or h a l o p e n d o l m a y p r o v i d e f u r t h e r e v i d e n c e regarding t h e m e c h a n i s m of a c t i o n o f these drugs a n d m a y f u r t h e r suggest t h a t a d i f f e r e n c e m the b a l a n c e b e t w e e n d o p a m m e a n d o t h e r t r a n s m i t t e r s a c c o u n t s for s o m e o f t h e d i f f e r e n c e s b e t w e e n the drugs. Specifically, we lnvest~gated the a b d l t y o f t h e s e drugs to antagomze the aggression p r o d u c e d by a p o m o r p h m e [15] B o t h c o m p o u n d s have b e e n s h o w n to have a n t l a g g r e s s l o n p r o p e r t i e s in several m o d e l s of drugi n d u c e d aggression [ 5 , 1 5 ] .

Dopamlnerglc-chohnerg,c interaction

Aggression

METHOD Male, Long-Evans rats ( 3 7 5 - 4 7 5 g) were t e s aggression by placing t h e m in g r o u p s o f 4 in a chain × 19.5 × 19 5 c m ) 5 m m a f t e r an m t r a p e r l t o n e a l lr of 20 m g / k g o f a p o m o r p h m e This dose o f apom, was c h o s e n f r o m p r e v i o u s e x p e r i m e n t s m w h i c h s h o w n to p r o d u c e m a x i m a l aggression [ 5 , 1 1 ] . "lwere o b s e r v e d for 1 h r d u r i n g w h i c h t~me 3 param, aggression were m e a s u r e d as described b y Lal [ 10] were a t t a c k s or b~tes b y o n e a n i m a l against a n o t t d u r a t i o n of aggressive p o s t u r i n g (rearing b y pairs c a n d v o c a h z a t l o n s , w h i c h were a u t o m a t i c a l l y count, voice o p e r a t e d relay m o d i f i e d to d e t e c t s o u n d in tl" o f 2 4 0 0 - 4 8 0 0 Hz T h e r e h a b x h t y o f t h e s e measu b e e n d e m o n s t r a t e d an several r e c e n t r e p o r t s (see [5,1 Prior to t h e r e j e c t i o n of a p o m o r p h m e , o n e or r the f o l l o w i n g drugs were rejected h a l o p e n d o l (coul McNeil L a b o r a t o r t e s and J a n s s e n P h a r m a c e u t l c a peromlde (R4714) (courtesy of Janssen Pharmac morphine, dexetlmlde (R16470) (courtesy of P h a r m a c e u t l c a ) , n a l o x o n e or saline A series o f ranging f r o m i n e f f e c t i v e to larger effective doses o f a were utdazed in this s t u d y T h e v o l u m e of mject~o drugs ( o r saline) was 1 m l / k g in all cases. T h e d r u freshly d~ssolved m saline before use e x c e p t for hale a n d o x y p e r o m l d e w h i c h were freshly p r e p a r e d lr t a r t a r i c acid. Morphine and oxyperomlde were Injected peratoneally 45 m m b e f o r e testing, while haloperac rejected m t r a p e r l t o n e a l l y 2 h r b e f o r e testing p r e t r e a t m e n t t i m e s were based o n pilot e x p e r l m w h i c h it was d e t e r m i n e d t h a t t h e peak drug e f f e c t o~

Present Address Department of Pharmacology, Michigan State University, E. Lansing, MI 48824 639

640

G I A N U T S O S AN TABLE

I

EFFECT OF DRUGS ON APOMORPH[NE-INDUCED AGGRESSION*

Drug? Vehicle Halopendol

Oxyperomtde

Sahne Morphine

Dose (mg/kg)

N$

-0 63 1 25 25 I 25 25 50 -5 10

5 2 5 5 2 5 5 5 5 5

Aggressive Responses/Hour (Mean +_ SE/group) Rearing Vocahzatlons

Attacks 61 ~ 9 59 _+ 5 28 + 8§ 2 + 2§ 52 +_ 2 15 +_ 6§ 2 _+ 2§ 58 ± 10 28 _+ 11§ 1 ± 1§

2750 +_ 251 2358 ± 756 2358 ± 544 89_+ 89§ 2621 _+ 220 1163 _+ 510§ 33 _+ 33§ 1787 z 301 1150 ± 285 30_* 30§

2219 1351 1190 17 889 386 25 1188 702 1163

_+ 204 ± 97 _+ 487 _+ 15§ -* 95 -+ 148§ +- 25§ ± 252 ± 221 ± 196

*Apomorphme (20 mg/kg) was rejected into all groups ?Halopendol was injected two hours before testing while oxyperom~de was rejected 40 mm before testing :~Numbe~ of groups [four rats per group) tested §Sigmficantly different (p<0.05) from sahne control (Dunnet's Test) a f t e r t h e s e p r e t r e a t m e n t s D e x e t i m l d e and n a l o x o n e were rejected s u b c u t a n e o u s l y , 35 or 10 m i n b e f o r e testing, respectively. These p r e t r e a t m e n t t i m e s were also b a s e d o n pilot e x p e r i m e n t s H a l o p e r i d o l xs a well k n o w n n e u r o l e p t i c , while o x y p e r o m l d e is a n e u r o l e p t i c a g e n t with little if a n y c a t a l e p t i c activity at the doses used in this s t u d y (C J. E Niemegeers, p e r s o n a l c o m m u n i c a t i o n ) . D e x e t l m I d e is a c e n t r a l l y a c t i n g a n t l c h o l i n e r g i c drug [ 7 ] . T h e results were a n a l y z e d statistically using D u n n e t ' s Test [ 2 1 ]

These results suggested t h a t a cholinergic con" c o n t r i b u t e d to t h e anti-aggression a c t i o n of t h e leptacs. In o r d e r to test this a s s u m p t i o n , a ma effective dose of o x y p e r o m i d e (2 5 mg/kg) was co w i t h a marginally effective dose (2 m g / k g ) cholinergic drug, piIocarpine ( p r e v i o u s l y d e t e r m i n e pilot e x p e r i m e n t s ) The c o m b i n a t i o n of these , m a r k e d l y r e d u c e d t h e aggression p r o d u c e d by apom, ( T a b l e 3)

RESULTS F o l l o w i n g t h e i n j e c t i o n of 20 m g / k g of a p o m o r p h a n e , t h e rats, as e x p e c t e d , d e m o n s t r a t e d a high degree of aggression c h a r a c t e r i z e d by long intervals of rearing a c c o m p a n i e d by loud v o c a h z a t i o n , f r e q u e n t biting and periods o f boxing. These b e h a v i o r s were a n t a g o n i z e d b y all 3 o f t h e test c o m p o u n d s utilized m thts s t u d y H a l o p e r i d o l was m a x i m a l l y effective at a dose of 2.5 mg/kg, oxyperom~de at a dose of 5 m g / k g and m o r p h i n e at a dose of 10 m g / k g ( T a b l e 1) Naloxone, which had no effect on apomorphlne-mduced aggression o n Its own, was able to a n t a g o n i z e t h e b l o c k a d e o f aggression p r o d u c e d b y m o r p h i n e ( T a b l e 2), so t h a t h i g h levels o f fighting r e s u l t e d a f t e r t h e c o m b i n e d a d m i n i s t r a t i o n o f m o r p h i n e + n a l o x o n e + a p o m o r p h m e . However, this n a r c o t i c a n t a g o n i s t failed to alter t h e b l o c k a d e of aggressaon p r o d u c e d b y h a l o p e r i d o l or o x y p e r o m i d e . In c o n t r a s t t o these results, the a n t l m u s c a r i n l c c o m p o u n d , d e x e t i m i d e , partially a n t a g o n i z e d the b l o c k a d e o f aggression p r o d u c e d b y e i t h e r n e u r o l e p t l c ( T a b l e 2) T h e dose of d e x e t i m i d e w h i c h was effective in reversing t h e n e u r o l e p t i c e f f e c t (2.5 m g / k g ) a p p a r e n t l y has h t t l e , if any, e f f e c t o n a p o m o r p h l n e - i n d u c e d aggression o n its o w n (G~anutsos and Lal, in p r e p a r a t i o n ) Larger doses o f d e x e t l m i d e r e t u r n e d the aggression to essentially saline c o n t r o l levels. However, even this large dose of d e x e t i m l d e was u n a b l e to p r e v e n t the anti-aggression a c t i o n of m o r p h i n e ( T a b l e 2).

T h e results of this s t u d y i n d i c a t e t h a t the ant~-ag[ a c t i o n of n e u r o l e p t l c s and m o r p h i n e m a y be differ antagonized by different compounds Both morph the n e u r o l e p t l c s r e d u c e d the aggression i n d u c e d by dose of a p o m o r p h i n e . However, n a l o x o n e p r e v e n r e d u c t i o n o f a p o m o r p h i n e - i n d u c e d aggression prodl m o r p h i n e , b u t n o t b y h a l o p e r i d o l , while t h cholinergic, dexetamlde, reversed t h e effect of the lept~cs, b u t n o t t h a t of m o r p h i n e . Previously, d e m o n s t r a t e d t h a t n a r c o t i c a n t a g o n i s t s and ant~chol also d i f f e r e n t i a l l y a n t a g o m z e some b e h a v i o r a l ef[ n a r c o t i c s and neurolept~cs (see I n t r o d u c t i o n ) It sh, p o i n t e d o u t t h a t a p o m o r p h m e i n d u c e d aggression x~ an this s t u d y as a m o d e l of d o p a m l n e h y p e r a c t i v i t y 9, 1 1 ] ) a n d the results m a y be n o t g e n e r a h z e d to a] of aggresston. In t h e p r e s e n t s t u d y , n a l o x o n e and dexet~mtd s h o w n to selectively a n t a g o n i z e the a b I h t y of m o r p h neurolept~cs, respectively, to c o u n t e r a c t t h e bel effects resulting f r o m the a d m l m s t r a t ~ o n of a do agonlst A r e d u c t i o n of d o p a m m e r e c e p t o r act~vatior be c o n s i s t e n t with a b l o c k a d e of a p o m o r p h m e - i aggression, since a p o m o r p h m e IS b e h e v e d to , s t i m u l a t e d o p a m i n e r e c e p t o r s [ 1 , 1 3 ] a n d this f~ aggressive b e h a v i o r appears to be d e p e n d e n t o n do activity [4,5] B o t h n e u r o l e p t i c drugs [2,1 2] a n d m, [ 6 , 1 4 ] a p p a r e n t l y increase the t u r n o v e r of dopamJ c o n s e q u e n c e of r e d u c e d r e c e p t o r activity, b u t it

DISCUSSION

D R U G S AND A G G R E S S I O N TABLE 2 REVERSAL OF THE BLOCKADE OF APOMORPHINE-INDUCED AGGRESSION*

Pretreatment Drug

Dose (mg/kg)

Post-Treatment Drug

Sahne

--

Sahne

Haloper]dol

25

Sahne Dexehmlde

Dose (mg/kg)

N

Aggressive Responses/Hour (Mean _+ SE/groupl Attacks Realmg Vocahzatlon

--

5

47 ± 10

1633 = 315

1119 ± 306

3 2 6 3 3 3 4 4 3 3 3 3 3 6 5

3 18 14 45

± 3 ± 4 ± 3 ± 4 0 0 19 _+ 9 20 _+ 4 37 ± 13 0 0 1 _+ 0 0 4 ± 2 42 ± 5

71 _+ 71 986 ± 152 571 ± 191 1392 ± 209 0 0 615 ___ 278 562 ± 118 1087 ± 389 0 0 6 _+ 5 0 76 ± 52 1654 _+ 384

22 583 403 1214

Naloxone

-I 25 25 50 4.0 -1 25 25 5.0 4.0 -1 25 25 50 40

_+ 23 --_ 120 ± 109 ± 342 0 0 433 _+ 207 388 _+ 110 998 _+ 303 0 0 12 +_ 9 0 101 ± 51 1163 +_ 196

Naloxone

40

3

46 ±

2189 +_ 263

1283 _+ 107

Oxyperomlde

5

Naloxone Sahne Dexehmlde

Morphine

I0

Naloxone Sahne Dexetimlde

Sahne

--

5

*All groups were injected with apomorphme (20 mg/kg) following treatment with other drugs TABLE 3 EFFECT OF PILOCARPINE PLUS OXYPEROMIDE ON APOMORPHINE*-INDUCED AGGRESSION

Drug

Nt

Sahne Pfiocarpme:~ Oxyperomlde§ Pdocarpme~ + Oxyperomlde§

6 6 6 6

Aggresswe Responses/Hour (Mean _+ SE/group) Reanng Attacks (Secs) Vocahzatlon 53 ± 4 30 ± 6 28 __. 6 4 ± 3¶

2702 _ 122 1621 _+ 334 1410 +_ 434 465 ± 307¶

1693 __+-221 451 +- 88 745 ± 245 125 ±

94

r e d u c e a p o m o r p h m e - m d u c e d aggression These drl increase the release and t u r n o v e r o f a c e t y l c h o h n e ( a consequence of dopamlne receptor blockade [ Since c h o h n e r g l c s t i m u l a t i o n also r e d u c e s apom~ i n d u c e d aggression [ 5 ] , it is possible that the rel ACh by the n e u r o l e p t l c s c o n t r i b u t e s to their antl-agl activity. I n d e e d , it was s h o w n in this s t u d y t h a t cc t r e a t m e n t o f o x y p e r o m l d e and a c h o h n e r g l c e n h a n c e d the anti-aggression p r o p e r t y o f o x y p e Thus, a n t l c h o h n e r g l c drugs may partxally reverse th, o f the n e u r o l e p t i c s by c o u n t e r a c t i n g the e f f e c t s o f ACh The m e c h a n i s m by w h i c h m o r p h i n e blocks the slon (and r e d u c e s d o p a m m e r e c e p t o r a c t w l t y ) lS~ but appears to be d i f f e r e n t f r o m the a c t t o n o f halo M o r p h i n e may w o r k indirectly via s o m e n e u r o n a

*20 mg/kg of apomorphme m.lected into all groups tNumber of groups (4 rats per group)tested :~2 mg/kg 10 mm before testing §2 5 mg/kg 35 mm before testing ¶S~gmficantly different (p <0 05) from pdocarpme or oxyperom]de alone (by Test of lndwldual Comparisons, 21)

o t h e r t h a n direct r e c e p t o r b l o c k a d e , a l t h o u g h tt cluslon is speculative at this time. In a d d l h o n , 11 a p p e a r t h a t ACh is u m m p o r t a n t for th~s behavioral e m o r p h i n e suggesting t h a t m o r p h i n e d i s t u r b s the d o p a m m e / A C h balance m a m a n n e r u n h k e the neurc Lastly, it has b e e n d e m o n s t r a t e d t h a t ant~mu

a p p e a r t h a t t h e precise m e c h a m s m revolved is d i f f e r e n t for t h e s e t w o classes o f c o m p o u n d s , The n e u r o l e p t l c s are b e h e v e d to d i r e c t l y b l o c k d o p a m m e r e c e p t o r s [ 2,12] and this m a y a c c o u n t for their a b t h t y to

drugs m a y a n t a g o m z e s o m e o f the chnlcal the1 a c h v i t y o f a n t i - p s y c h o t i c drugs [ 16]. The relevanc~ p r e s e n t results in w h i c h the antl-aggressaon action n e u r o l p e h c s is simdarly a n t a g o m z e d by antl-mu c o m p o u n d s r e m a i n s to be established.

REFERENCES Anden, N E , A. Robenson, K Fuxe and T Hokfelt Evidence for dopamme receptor stimulation by apomorphme. J Pharm Pharmae. 19: 627-629, 1967

Anden, N. E, S. G Butcher, H Corrodl, K. Fux~ Ungerstedt. Receptor activity and turnover of dopa~ noradrenallne after neuroleptlcs Eur. J Pharn~ 303-314, 1970

642 3

Costall, B and R J. Naylor On catalepsy and catatoma and the predictability of the catalepsy test for neuroleptlc activity Psychopharrnacologta 34: 233-241, 1974 4 Elchelman, B. S and N B Thoa The aggressive monoamlnes Btol Psychzat. 6: 143-164, 1973 5. Glanutsos, G and H Lal. Drug-reduced aggression In Current Developments o7 Psychopharmacology, edited by W B Essman and L Valzelh New York Wiley (In press) 6 Gunne, L M, J Jonsson and K Fu×e Effects of morphine intoxication on brain catecholamme neurons Eur J Pharmac 5: 338-342, 1969 7 Janssen, P A J , C J E. Nlemegeers, K M L Schellekens, P Demoen, F M Lenaerts, J M. Van Neuten, I Van Wungaarden and J Brugmans Benzetlmlde and tts optical Isomers Arznetmittel Forsch 21:1365-1373, 1971 8 Kuschlnsky, K and O Hornyklewlcz Morphine catalepsy in the rat Relation to strlatal dopamme metabohsm Eltr J Pharmac. 1 9 : 1 1 9 - 1 2 2 , 1972 9 Lal, H Narcotic dependence, narcotic action and dopamme receptors. LlJeSct 17: 483-496, 1975 10 Lal, H Morphine withdrawal aggression In Methods zn Narcottc Research, edited by S Ehrenprels and A Neldle New York Marcel Dekker, 1975, pp 149-171 11 Lal, H , G Gmnutsos and S K Purl A comparison of narcotic analgesics w,th neuroleptlcs on behavioral measures of dopammerglc actwlty. Ltfe Scl. 17: 29-34, 1975 12 Nyback, H , Z Borzeckl and G. Sedvall. Accumulation and disappearance of catecholammes formed from tyrosme-I 4C in mouse brain Effect of some psychotroplc drugs Eur. J Pharmac 4: 395-402, 1968

G I A N U T S O S AN 13

14.

15 16

17. 18.

19

20

21.

Price, M. C T. and H. C. Flblger. Apomorphme and amine stereotypy after 6-hydroxydopamine lesions substantla nigra. Eur J Pharrnac 29: 249-252, 1974. Purl, S. K , C Reddy and H Lal Blockade of central d~ receptors by morphine Effects of haloperldol, apomorl benztropme. Res communs chem pathol Phar~ 389-401, 1973 Senault, B Comportment d'aggresslvlte mtraspeclflqu par l'apomorphme chez le rat Psvchopharmacolo 271-287, 1970 Slngh, M. M and S R Kay A comparative s halopendol and chlorpromazlne m terms of chmcaleff therapeutic reversal wtth benztroplne in schlzo Theoretical implications for potency differences amon leptlcs Psychopharmacologta 43:103 113, 1975. Stadler, H., K G Lloyd, M Gadea-Clrm and G Ba Enhanced strmtal acetylchohne release by chlorproma: its reversal by apomorphme. Brain Res 55: 476-480, 1 Trabucchi, M., D. Cheney, G. Racagni and E. Costa. ment of brain cholinerglc mechamsms m the ac chlorpromazme. Nature 249: 664-667, 1974 Wauquler, A , C J E Nlemegeers and H Lal. Dlf antagomsm by naloxone of inhibitory effects of hal and morphine on brain self-stimulation Psychopharm 37: 303-310, 1974 Wauquler, A , C J E Nlemegeers and H. Lal Dlf antagonism by the antlcholinerglc dexetlmlde of m effects of halopendol and fentanyl on brain self-stlrr Psychopharmacologta41: 229-235, 1975 Wmer, B J Stattstical Principles in Expertmental second edition New York McGraw-Hill, 1971