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Similar effect of estradiol and haloperidol on experimental tardive dyskinesia in monkeys
lasychoneuroendocrinology, Vol. 9, No. 4, pp. 3 7 5 - 379, 1984 Printed in Great Britain.
0306-4530/84 $3.00 + 0.00 © 1984Pergamon Press Ltd.
SIMILAR EFFECT OF ESTRADIOL AND HALOPERIDOL ON EXPERIMENTAL TARDIVE DYSKINESIA IN MONKEYS PAUL J. BI~DARD,* Rl~Nl~ BOUCHER,* MICHEL DAIGLEt and THI~RI~SEDI PAOLOt Laboratoire de Neurobiologie, *Department of Anatomy, Laval University, tDepartment of Molecular Endocrinology, Centre Hospitalier de l'Universit~ Laval Qu6bec, Qu6., Canada
(Received 29 June 1983; in final form 2 April 1984) SUMMARY In a group of ovariectomizedmonkeys, a persistent buccolingual dyskinesia resembling tardive dyskinesia was induced by an upper midbrain lesion. This dyskinesia was increased by apomorphine. A single dose of haloperidoi (1 mg/kg) reduced the effect of apomorphine after 24 hours and caused an increase in CSF homovanillic acid. Fifteen days later, however, the response to apomorphine was markedly enhanced. Estradiol benzoate (0.5 mg sc) had a similar biphasic effect, although of lesser magnitude. In a different group of lesioned but non-dyskineticanimals, the CSF concentration of HVA also was elevated 24 hours after estradiol. These results support our hypothesis that estradiol shares several properties with neuroleptics, and in particular, reduces, then enhances the sensitivity of striatal dopaminergic receptors. INTRODUCTION WE PREVIOUSLYhave reported that estrogens administered orally to patients could reduce the intensity of tardive dyskinesia and DOPA-induced dyskinesia (B6dard et al., 1977; 1979). Our findings have been confirmed by Villeneuve et al. (1980) and Koller et al. (1982). We then suggested that estrogens could decrease dopamine function at the level of the striatum, in a manner similar to a neuroleptic (B~dard et al., 1981). This claim was supported by a large body of pharmacological evidence showing that estradiol can antagonize the effect of dopaminergic agonists in several behavioral models such as circling (B~dard et al., 1978; Euvrard et al., 1980), stereotypy (Naik et al., 1978; Early & Leonard, 1978), and locomotor activity (B~dard et al., 1980), as well as potentiate haloperidol-induced catalepsy (Chiodo et al., 1979). Others, however, have reported conflicting results, demonstrating facilitation by estradiol of circling (Hruska & Silbergeld, 1980) and stereotypy (Lal & Sourkes, 1972; Nausieda et al., 1979a; Chiodo et al., 1981) induced by a dopamine agonist. This facilitation appeared consistent with the well-known observation that estrogen-containing contraceptives may induce chorea in susceptible women (Fernando, 1966; Bickerstaff, 1975; Barber et al., 1976; Nausieda et al., 1979b). We therefore were facing two lines of pharmacological and clinical evidence claiming opposite behavioral actions of estradiol. Biochemically, estradiol was shown to induce a 20% increase of [3H]spiroperidol binding to rat striatal membranes (Di Paolo et al., 1979; 1982; Hruska & Silbergeld, 1980). Such an increase, although suggesting some effect of estradiol on dopamine receptors, could be interpreted as the basis of the behavioral Correspondence to: Paul J. B6dard, Laboratoire de Neurobiologie, H6pital de l'Enfant-J~sus, 1401 18e Rue, Quebec, Qua., Canada GIJ IZA. Supported by the Medical Research Council of Canada and the Fonds de la Recherche en Sant6 du Qu6bec. 375
376
PAUL J. BI~DARD, RENI~ BOUCHER, MICHEL DAIGLE and THI~RI~SE D1 PAOLO
f a c i l i t a t i o n o r m e r e l y as a c o n s e q u e n c e administration.
of receptor
blockade
following haloperidol
These views are not incompatible if one remembers that haloperidol or other n e u r o l e p t i c s will i n i t i a l l y b l o c k d o p a m i n e receptors but trigger a reaction of supersensitivity manifested by an increased response to dopamine agonists (Smith & D a v i s , 1976) a n d a p r o l i f e r a t i o n o f [ 3 H ] s p i r o p e r i d o l b i n d i n g sites ( B u r t e t a l . , 1977). I t t h e n c a n b e a r g u e d t h a t t h e r e p o r t e d d i f f e r e n c e s a r e d u e in l a r g e p a r t t o t h e d o s e g i v e n , b u t m o s t l y t o t h e t i m e o f o b s e r v a t i o n a f t e r t h e l a s t d o s e , as s u g g e s t e d o r i g i n a l l y b y G o r d o n (1980). We therefore decided to test the hypothesis that estradiol and haloperidol would have a similar biphasic effect of inhibition followed by facilitation on the apomorphine-induced p o t e n t i a t i o n o f l i n g u a l d y s k i n e s i a in t h e m o n k e y . T h e d y s k i n e s i a c a n b e p r o d u c e d b y a n u p p e r m i d b r a i n a n d c a u d a l d i e n c e p h a l i c l e s i o n . It is c h a r a c t e r i z e d m o s t l y b y t o n g u e p r o t r u s i o n a n d t o n g u e r o l l i n g . L a t e r a l j a w m o v e m e n t s a l s o o c c u r . T h e d y s k i n e s i a is enhanced by dopamine agonists and decreased by antagonists. METHODS Twelve female monkeys (M. fascicularis) underwent a left electrolytic lesion at the stereotactic coordinates A. 8.5, L. 1.5, V. -1 under ketamine anesthesia. Ten animals also were ovariectomized simultaneously; the other two were ovariectomized a year after the brain surgery. In the days following recovery, a buccolingual dyskinesia was noticed in five animals. In previous experiments (B6dard et al., 1981, 1982), it was found that the dyskinesia could be increased by excitement but also by l -DOPA (100 mg/kg iv), amphetamine sulfate (0.3 mg/kg im) and apomorphine (0.01 to 0.04 mg/kg sc). It was completely abolished by haloperidol (1 mg/kg im). One animal died after a pharmacological experiment. Its brain was analyzed histologically, and the lesion was found to involve the left parafascicular nucleus and the habenulo-interpeduncular tract, causing ipsilateral cell loss in the habenula. The substantia nigra was not involved. The potentiation of the lingual dyskinesia with dopaminergic agents was studied with the animals sitting in a restraining chair. A trained observer facing the monkey recorded, with the help of an electronic time-event counter, all tongue protrusions beyond the line of the teeth. Only the tongue movements were recorded because they are easier to quantify and for trained observers were definitely abnormal for monkeys. In the present experiment the dyskinesia was recorded from 15 min before to 60 min after the injection of apomorphine (0.02 mg/kg). Apomorphine was chosen because in previous experiments it produced the most reproducible increase in lingual dyskinesia (B~dard et al., 1981; 1982). We also had established in those experiments that the effect of apomorphine on the dyskinesia was dose-dependent in the range of 0.01, 0.02 and 0.04 mg/kg sc. The same experiments also showed that the response to various doses of apomorphine was stable for a given dose over several weeks (B6dard et aL, 1981; 1982). At the end of each period of observation, we had a count of the number of dyskinesic movements on one channel of the time-event counter and on the other the cumulative "dyskinesia time". However, the present report will deal only with "dyskinesia time" because, under apomorphine, the animal often had periods of several seconds when its tongue twisted out of its mouth without interruption. It therefore was concluded that dyskinesia time was a more reliable index of dopaminergic potentiation. The experiments were done between six months and three years after stereotactic surgery and ovariectomy. The design was as follows: the dyskinesia-potentiating effect of apomorphine (0.02 mg/kg) was tested repeatedly in the same four monkeys in two separate experiments 10 months apart. In each experiment, the first response to apomorphine was used as baseline. Immediately after the first apomorphine test, the four monkeys received in the first experiment estradiol benzoate (0.5 mg sc) and in the second experiment haloperidol (1 mg/kg im). The response to apomorphine then was tested again after 24 hours, 3 days, 6 - 7 days (estradiol only), 14 days and 28 - 30 days. At the time of the haloperidol experiment all dyskinetic animals also underwent a lumbar puncture, in their chairs, under local anesthesia before each of the first four apomorphine tests. One ml of cerebrospinal fluid (CSF) was taken out for determination of homovanillic acid (HVA) by high pressure liquid chromatography with electrochemical detection. Since no CSF had been obtained during the estradiol experiment, lumbar
SIMILAR EFFECT OF ESTRADIOLAND HALOPERIDOLON EXPERIMENTAL TARDIVE DYSKINESIAIN MONKEYS 377 punctures were performed in another group o f four lesioned but non-dyskinetic monkeys (same coordinates), before and after an injection of estradiol benzoate (0.5 m g sc).
RESULTS
As seen in Fig. 1, both estradiol and haloperidol markedly reduced (by 75070) the efficacy of a p o m o r p h i n e after 24 hours. At this time, no overt behavioral effect was seen in the estradiol-treated animals. Twenty-four hours after haloperidol, the animals appeared somewhat calmer than usual but were not sedated and were otherwise normal. At 14 days there was a rebound increase in the response to a p o m o r p h i n e and a return towards baseline at one month. The CSF H V A values were significantly elevated 24 hours after both estradiol and haloperidol, at the time of the reduced efficacy of apomorphine, and were decreased thereafter. HALOPERIDOL %
* P < O.O5
**
** P< 0.01
C.S.F. 200
600
,~
-i<
,
~ 500
100 ~" = 400 .E e 300 w e _¢ 200, ¢
~ 100
O
n'- N II O
1
7
14
28
(Days)
i~.s.~.
ESTRADIOL
% 200
~
z 15C
•4 0
< :3
'~ 100, a
'20
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'7, 50'
O
1
3
7
14
30
(Days)
FIG. 1. The top graph describes the effect of haloperidol (1 m g / k g im) and the bottom graph the effect of estradiol (0.5 mg sc) on the a p o m o r p h i n e (0.02 m g / k g sc) potentiation of lingual dyskinesia in monkeys. Each bar is the average "dyskinesia t i m e " _+ S.E.M. recorded in four monkeys during 75 min. The response to the first test was arbitrarily set as 100°70; the other values are based on this initial test. On the abscissa is the n u m b e r of days after the initial a p o m o r p h i n e test. Above each set of bars are shown (line graph) the CSF H V A levels immediately before the apomorphine test (corresponding values on the right ordinate). The CSF H V A values shown in connection with the estradiol experiment were obtained from a different group of female ovariectomized monkeys also bearing the same type of brain lesion but without dyskinesia. Significance levels were determined by paired t-tests (treatment vs baseline).
378
PAUL J. BI~DARD, RENI~ BOUCHER, MICHEL DAIGLE and THI~RI~SE DI PAOLO DISCUSSION
Our results demonstrate that estradiol and haloperidol can alter in a similar biphasic manner the response to apomorphine in a monkey model of lingual dyskinesia. They provide indirect evidence of an inhibition of dopaminergic transmission at 24 hours, followed by facilitation after two weeks, which lasts approximately two weeks. An increased HVA level in the CSF at the time of the inhibition (24 hours) also occurred after both compounds and suggests increased dopamine turnover consequent to receptor blockade. No clear decrease in HVA was seen at 14 days, but HVA unfortunately could not be measured 14 days after estradiol. Moreover, we may have missed this effect after haloperidol, due to the small number of animals. A similar biphasic pattern has been reported after estradiol in rats (Joyce et al., 1982; Gordon, 1980); however, the cycle was shorter, probably reflecting species differences. The increased [3H]spiroperidol binding after both substances (Di Paolo et al., 1979; B~dard et al., 1981) also underlines the similarities between estradiol and haloperidol. It should be noted, however, that in behavioral tests as well as in biochemical studies the effect of estradiol is weaker than that of haloperidol. Although it could be argued that the modification of the effect of apomorphine might be due to a pharmacokinetic effect, it is unlikely that changes in HVA levels or number of striatal dopamine receptors could be explained by this mechanism. Taken together, these results may be interpreted as suggesting that, in a single dose, estradiol affects postsynaptic dopamine receptors as a weak neuroleptic would do. One important difference, however, is that estradiol does not seem capable of displacing [3H]spiroperidol in rat striatal membranes (Di Paolo, unpublished data). Other explanations besides a neuroleptic-like effect of estradiol may be considered to explain this biphasic effect. For instance, estradiol could affect pre- and posbsynaptic dopamine receptors at different intervals, with resulting opposite effects. Estradiol (and haloperidol) could affect the release of another substance (prolactin for instance) which might in turn be responsible for some of the observed effects. Finally, part of the effect of estradiol could be due to an estrogen metabolite. In this respect, catechol-estrogens appear particularly interesting as they seem capable of interacting with membrane aminergic receptors (Schaeffer & Hsueh, 1979). Their short half-life, however, make them difficult to study pharmacologically (MacLusky et al., 1981). A better understanding of this intricate relationship between hormones and neurotransmitters may help resolve the aforementioned contradictory reports on the clinical effects of hormones on dyskinesia (B~dard et al., 1977; 1979; Villeneuve et al., 1980; Koller et al., 1982; Barber et al., 1976; Nausieda et al., 1979a). REFERENCES BARBER, P. V., ARNOLD, A. G. • EVANS, G. 0976) Recurrent hormone-depending chorea: effects of estrogens and progesterone. Clin. Endocr. 5, 291 - 2 9 3 . BI~DARD, P. J., LANGELIER, P. & VILLENEUVE, A. (1977) Estrogens and the extrapyramidal system. Lancet ii, 1367 - 1368. BI~DARD, P. J., DANKOVA, J., BOUCHER, R. & LANGELIER, P. (1978) Effect of estrogens on apomorphineinduced circling behavior in the rat. Can. J. Physiok Pharmac. 56, 538 - 541. BI~DARD, P. J., LANGEL1ER, P., DANKOVA, J., V1LLENEUVE, A., Dl PAOLO, T., BARDEN, N., LABRIE, F., BOISSIER, J. R. ~¢ EUVRARD, C. (1979) Estrogens, progesterone, and the extrapyramidal system. Adv. NeuroL 24, 411 - 422.
SIMILAR EFFECT OF F_~TRADIOLAND HALOPERIDOLON EXPERIMENTALTARDIVEDYSKINESlAIN MONKEYS 379 BI~DARD, P. J., BOUCHER, R., DANKOVA,J. & LANGELIER, P. (1980) Female sexual hormones influence motor behaviour in rats after lesion of the entopeduncular nucleus. Neurosci. Lett. 17, 89-94. BI~DARD, P. J., DI PAOLO, T., LANGELIER, e., POYET, P. & LABRIE, F. (1981) Behavioural and biochemical evidence of an effect of estradiol on striatal dopamine receptors. In Steroid Hormone Regulation o f the Brain, K. Fuxe, J.-A. Gustafsson and L. Wetterberg (Eds.), pp. 331 -339. Pergamon Press, Oxford. B~DARD, P. J., BOUCHER, R. • LAROCHELLE, L. (1982) Experimental tardive dyskinesia. Prog. NeuroPsychopsychopharmac. Biol. Psychiat. 6, 551- 554. BICKERSTAFF,E. R. (1975) Neurological Complications o f Oral Contraceptives, p. 69. Clarendon Press, Oxford• BORT, D. R., CREESE, I. & SNYDER, S. H. (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain• Science 197, 326- 328. CHIODO, L. A., CAGGIULA,A. R. & SALLER, C. F. (1979) Estrogen increases both spiperone-induced catalepsy and brain levels of [DH]spiperone in the rat. Brain Res. 172, 360-366. CHIODO, k., CAGGIULA,A. R. & SALLER, C. F. (1981) Estrogens potentiate the stereotypy induced by dopamine agonists in the rat. Life ScL 28, 827 - 835. DI PAOLO, T., CARMICHAEL, R., LABRIE, F. (~ RAYNAUD, J. P. (1979) Effects of estrogens on the characteristics of [DH]RU24213 binding in rat anterior pituitary gland and brain. Molec. Cell. Endocr. 16, 9 9 - 112. nl PAOLO, T., BI~DARD,P. J., DUPONT, k., POYET, P. & LABRIE, F. (1982) Effect of estradiol on intact and denervated striatal dopamine receptors and on dopamine levels: a biochemical and behavioral study. Can. J. Physiol. Pharmac. 60, 350- 357. EARLY, C. J. (~ LEONARD, B. E. (1978) Behavioural studies on the effects of D-amphetamine and estradiol benzoate alone and in combination. Psychopharmacology 56, 179 - 183. EUVRARD, C., OBERLANDER, C. & BOISSIER, J. R. (1980) Antidopaminergic activity of estrogens on prolactin release at the pituitary level in vivo. J. Pharmac. exp. ther. 214, 179- 185. FERNANDO, S. J. M. (1966) An attack of chorea complicating oral contraceptive therapy• Practitioner 197, 210-211. GORDON, J. H. (1980) Modulation of apomorphine-induced stereotypy by estrogen: time course and dose response. Brain Res. Bull. s, 679- 682. HRUSKA, R. E. & SILBERGELD, E. K. (1980) Increased dopamine receptor sensitivity after estrogen treatment using the rat .rotation model• Science 209, 1466- 1468. JOYCE, J. N., SMITH, R. L. and VAN HARTESVELD (1982) Estradiol suppresses, then enhances intracaudate dopamine-induced contralateral deviation. Eur. J. Pharmac. 81, 117 - 122. KOLLER, W. C., BARR, A. & BIARY, N. (1982) Estrogen treatment of dyskinetic disorders• Neurology 32, 547 - 550. LAL, S. & SOURKES,T. L. (1972) Potentiation of the amphetamine stereotypy in rats by neuroleptics and other agents• Archs. int. Pharmac. 199, 289- 301. MACLUSKY, N. J., NAFTOL1N, F., KREY, L. C. and FRANKS, S. (1981) The catechol estrogens• J. Steroid Biochem. 15, 111 - 124. NAIK, S. R., KELHAR, M. R. & SETH, O. K. (1978) Attenuation of stereotyped behavior by sex steroids. Psychopharmacology 57, 211 - 214. NAUSIEDA, P. A., KOLLER, W. C., WEINER, W. J. and KLAWANS, H. L. (1979a) Chorea induced by oral contraceptives. Neurology 29, 1605 - 1609. NAUSIEDA, P. A., KOLLER, W. C., WEINER, W. J. t~ KLAWANS, H. L. (1979b) Modification of postsynaptic dopaminergic sensitivity by female sex hormones• Life Sci. 25, 521 -526. SCHAEFFER, J. M. t~ HSUEH, A. J. W. (1979) 2-Hydroxy estradiol interaction with dopamine receptor binding in rat anterior pituitary. J. biol. Chem. 254, 5606-5608. SMITH, R. & DAVIS, J. (1976) Behavioral evidence for supersensitivity after chronic administration of haloperidol, clozapine and thioridazine. Life Sci. 19, 725 - 732. VILLENEUVE, A., CAZEJUST, T. & COTI~, M. (1980) Estrogens in tardive dyskinesia in male psychiatric patients. Neuropsychobiology 6, 145 - 151.
0306-4530/84 $3.00 + 0.00 © 1984Pergamon Press Ltd.
SIMILAR EFFECT OF ESTRADIOL AND HALOPERIDOL ON EXPERIMENTAL TARDIVE DYSKINESIA IN MONKEYS PAUL J. BI~DARD,* Rl~Nl~ BOUCHER,* MICHEL DAIGLEt and THI~RI~SEDI PAOLOt Laboratoire de Neurobiologie, *Department of Anatomy, Laval University, tDepartment of Molecular Endocrinology, Centre Hospitalier de l'Universit~ Laval Qu6bec, Qu6., Canada
(Received 29 June 1983; in final form 2 April 1984) SUMMARY In a group of ovariectomizedmonkeys, a persistent buccolingual dyskinesia resembling tardive dyskinesia was induced by an upper midbrain lesion. This dyskinesia was increased by apomorphine. A single dose of haloperidoi (1 mg/kg) reduced the effect of apomorphine after 24 hours and caused an increase in CSF homovanillic acid. Fifteen days later, however, the response to apomorphine was markedly enhanced. Estradiol benzoate (0.5 mg sc) had a similar biphasic effect, although of lesser magnitude. In a different group of lesioned but non-dyskineticanimals, the CSF concentration of HVA also was elevated 24 hours after estradiol. These results support our hypothesis that estradiol shares several properties with neuroleptics, and in particular, reduces, then enhances the sensitivity of striatal dopaminergic receptors. INTRODUCTION WE PREVIOUSLYhave reported that estrogens administered orally to patients could reduce the intensity of tardive dyskinesia and DOPA-induced dyskinesia (B6dard et al., 1977; 1979). Our findings have been confirmed by Villeneuve et al. (1980) and Koller et al. (1982). We then suggested that estrogens could decrease dopamine function at the level of the striatum, in a manner similar to a neuroleptic (B~dard et al., 1981). This claim was supported by a large body of pharmacological evidence showing that estradiol can antagonize the effect of dopaminergic agonists in several behavioral models such as circling (B~dard et al., 1978; Euvrard et al., 1980), stereotypy (Naik et al., 1978; Early & Leonard, 1978), and locomotor activity (B~dard et al., 1980), as well as potentiate haloperidol-induced catalepsy (Chiodo et al., 1979). Others, however, have reported conflicting results, demonstrating facilitation by estradiol of circling (Hruska & Silbergeld, 1980) and stereotypy (Lal & Sourkes, 1972; Nausieda et al., 1979a; Chiodo et al., 1981) induced by a dopamine agonist. This facilitation appeared consistent with the well-known observation that estrogen-containing contraceptives may induce chorea in susceptible women (Fernando, 1966; Bickerstaff, 1975; Barber et al., 1976; Nausieda et al., 1979b). We therefore were facing two lines of pharmacological and clinical evidence claiming opposite behavioral actions of estradiol. Biochemically, estradiol was shown to induce a 20% increase of [3H]spiroperidol binding to rat striatal membranes (Di Paolo et al., 1979; 1982; Hruska & Silbergeld, 1980). Such an increase, although suggesting some effect of estradiol on dopamine receptors, could be interpreted as the basis of the behavioral Correspondence to: Paul J. B6dard, Laboratoire de Neurobiologie, H6pital de l'Enfant-J~sus, 1401 18e Rue, Quebec, Qua., Canada GIJ IZA. Supported by the Medical Research Council of Canada and the Fonds de la Recherche en Sant6 du Qu6bec. 375
376
PAUL J. BI~DARD, RENI~ BOUCHER, MICHEL DAIGLE and THI~RI~SE D1 PAOLO
f a c i l i t a t i o n o r m e r e l y as a c o n s e q u e n c e administration.
of receptor
blockade
following haloperidol
These views are not incompatible if one remembers that haloperidol or other n e u r o l e p t i c s will i n i t i a l l y b l o c k d o p a m i n e receptors but trigger a reaction of supersensitivity manifested by an increased response to dopamine agonists (Smith & D a v i s , 1976) a n d a p r o l i f e r a t i o n o f [ 3 H ] s p i r o p e r i d o l b i n d i n g sites ( B u r t e t a l . , 1977). I t t h e n c a n b e a r g u e d t h a t t h e r e p o r t e d d i f f e r e n c e s a r e d u e in l a r g e p a r t t o t h e d o s e g i v e n , b u t m o s t l y t o t h e t i m e o f o b s e r v a t i o n a f t e r t h e l a s t d o s e , as s u g g e s t e d o r i g i n a l l y b y G o r d o n (1980). We therefore decided to test the hypothesis that estradiol and haloperidol would have a similar biphasic effect of inhibition followed by facilitation on the apomorphine-induced p o t e n t i a t i o n o f l i n g u a l d y s k i n e s i a in t h e m o n k e y . T h e d y s k i n e s i a c a n b e p r o d u c e d b y a n u p p e r m i d b r a i n a n d c a u d a l d i e n c e p h a l i c l e s i o n . It is c h a r a c t e r i z e d m o s t l y b y t o n g u e p r o t r u s i o n a n d t o n g u e r o l l i n g . L a t e r a l j a w m o v e m e n t s a l s o o c c u r . T h e d y s k i n e s i a is enhanced by dopamine agonists and decreased by antagonists. METHODS Twelve female monkeys (M. fascicularis) underwent a left electrolytic lesion at the stereotactic coordinates A. 8.5, L. 1.5, V. -1 under ketamine anesthesia. Ten animals also were ovariectomized simultaneously; the other two were ovariectomized a year after the brain surgery. In the days following recovery, a buccolingual dyskinesia was noticed in five animals. In previous experiments (B6dard et al., 1981, 1982), it was found that the dyskinesia could be increased by excitement but also by l -DOPA (100 mg/kg iv), amphetamine sulfate (0.3 mg/kg im) and apomorphine (0.01 to 0.04 mg/kg sc). It was completely abolished by haloperidol (1 mg/kg im). One animal died after a pharmacological experiment. Its brain was analyzed histologically, and the lesion was found to involve the left parafascicular nucleus and the habenulo-interpeduncular tract, causing ipsilateral cell loss in the habenula. The substantia nigra was not involved. The potentiation of the lingual dyskinesia with dopaminergic agents was studied with the animals sitting in a restraining chair. A trained observer facing the monkey recorded, with the help of an electronic time-event counter, all tongue protrusions beyond the line of the teeth. Only the tongue movements were recorded because they are easier to quantify and for trained observers were definitely abnormal for monkeys. In the present experiment the dyskinesia was recorded from 15 min before to 60 min after the injection of apomorphine (0.02 mg/kg). Apomorphine was chosen because in previous experiments it produced the most reproducible increase in lingual dyskinesia (B~dard et al., 1981; 1982). We also had established in those experiments that the effect of apomorphine on the dyskinesia was dose-dependent in the range of 0.01, 0.02 and 0.04 mg/kg sc. The same experiments also showed that the response to various doses of apomorphine was stable for a given dose over several weeks (B6dard et aL, 1981; 1982). At the end of each period of observation, we had a count of the number of dyskinesic movements on one channel of the time-event counter and on the other the cumulative "dyskinesia time". However, the present report will deal only with "dyskinesia time" because, under apomorphine, the animal often had periods of several seconds when its tongue twisted out of its mouth without interruption. It therefore was concluded that dyskinesia time was a more reliable index of dopaminergic potentiation. The experiments were done between six months and three years after stereotactic surgery and ovariectomy. The design was as follows: the dyskinesia-potentiating effect of apomorphine (0.02 mg/kg) was tested repeatedly in the same four monkeys in two separate experiments 10 months apart. In each experiment, the first response to apomorphine was used as baseline. Immediately after the first apomorphine test, the four monkeys received in the first experiment estradiol benzoate (0.5 mg sc) and in the second experiment haloperidol (1 mg/kg im). The response to apomorphine then was tested again after 24 hours, 3 days, 6 - 7 days (estradiol only), 14 days and 28 - 30 days. At the time of the haloperidol experiment all dyskinetic animals also underwent a lumbar puncture, in their chairs, under local anesthesia before each of the first four apomorphine tests. One ml of cerebrospinal fluid (CSF) was taken out for determination of homovanillic acid (HVA) by high pressure liquid chromatography with electrochemical detection. Since no CSF had been obtained during the estradiol experiment, lumbar
SIMILAR EFFECT OF ESTRADIOLAND HALOPERIDOLON EXPERIMENTAL TARDIVE DYSKINESIAIN MONKEYS 377 punctures were performed in another group o f four lesioned but non-dyskinetic monkeys (same coordinates), before and after an injection of estradiol benzoate (0.5 m g sc).
RESULTS
As seen in Fig. 1, both estradiol and haloperidol markedly reduced (by 75070) the efficacy of a p o m o r p h i n e after 24 hours. At this time, no overt behavioral effect was seen in the estradiol-treated animals. Twenty-four hours after haloperidol, the animals appeared somewhat calmer than usual but were not sedated and were otherwise normal. At 14 days there was a rebound increase in the response to a p o m o r p h i n e and a return towards baseline at one month. The CSF H V A values were significantly elevated 24 hours after both estradiol and haloperidol, at the time of the reduced efficacy of apomorphine, and were decreased thereafter. HALOPERIDOL %
* P < O.O5
**
** P< 0.01
C.S.F. 200
600
,~
-i<
,
~ 500
100 ~" = 400 .E e 300 w e _¢ 200, ¢
~ 100
O
n'- N II O
1
7
14
28
(Days)
i~.s.~.
ESTRADIOL
% 200
~
z 15C
•4 0
< :3
'~ 100, a
'20
o
'7, 50'
O
1
3
7
14
30
(Days)
FIG. 1. The top graph describes the effect of haloperidol (1 m g / k g im) and the bottom graph the effect of estradiol (0.5 mg sc) on the a p o m o r p h i n e (0.02 m g / k g sc) potentiation of lingual dyskinesia in monkeys. Each bar is the average "dyskinesia t i m e " _+ S.E.M. recorded in four monkeys during 75 min. The response to the first test was arbitrarily set as 100°70; the other values are based on this initial test. On the abscissa is the n u m b e r of days after the initial a p o m o r p h i n e test. Above each set of bars are shown (line graph) the CSF H V A levels immediately before the apomorphine test (corresponding values on the right ordinate). The CSF H V A values shown in connection with the estradiol experiment were obtained from a different group of female ovariectomized monkeys also bearing the same type of brain lesion but without dyskinesia. Significance levels were determined by paired t-tests (treatment vs baseline).
378
PAUL J. BI~DARD, RENI~ BOUCHER, MICHEL DAIGLE and THI~RI~SE DI PAOLO DISCUSSION
Our results demonstrate that estradiol and haloperidol can alter in a similar biphasic manner the response to apomorphine in a monkey model of lingual dyskinesia. They provide indirect evidence of an inhibition of dopaminergic transmission at 24 hours, followed by facilitation after two weeks, which lasts approximately two weeks. An increased HVA level in the CSF at the time of the inhibition (24 hours) also occurred after both compounds and suggests increased dopamine turnover consequent to receptor blockade. No clear decrease in HVA was seen at 14 days, but HVA unfortunately could not be measured 14 days after estradiol. Moreover, we may have missed this effect after haloperidol, due to the small number of animals. A similar biphasic pattern has been reported after estradiol in rats (Joyce et al., 1982; Gordon, 1980); however, the cycle was shorter, probably reflecting species differences. The increased [3H]spiroperidol binding after both substances (Di Paolo et al., 1979; B~dard et al., 1981) also underlines the similarities between estradiol and haloperidol. It should be noted, however, that in behavioral tests as well as in biochemical studies the effect of estradiol is weaker than that of haloperidol. Although it could be argued that the modification of the effect of apomorphine might be due to a pharmacokinetic effect, it is unlikely that changes in HVA levels or number of striatal dopamine receptors could be explained by this mechanism. Taken together, these results may be interpreted as suggesting that, in a single dose, estradiol affects postsynaptic dopamine receptors as a weak neuroleptic would do. One important difference, however, is that estradiol does not seem capable of displacing [3H]spiroperidol in rat striatal membranes (Di Paolo, unpublished data). Other explanations besides a neuroleptic-like effect of estradiol may be considered to explain this biphasic effect. For instance, estradiol could affect pre- and posbsynaptic dopamine receptors at different intervals, with resulting opposite effects. Estradiol (and haloperidol) could affect the release of another substance (prolactin for instance) which might in turn be responsible for some of the observed effects. Finally, part of the effect of estradiol could be due to an estrogen metabolite. In this respect, catechol-estrogens appear particularly interesting as they seem capable of interacting with membrane aminergic receptors (Schaeffer & Hsueh, 1979). Their short half-life, however, make them difficult to study pharmacologically (MacLusky et al., 1981). A better understanding of this intricate relationship between hormones and neurotransmitters may help resolve the aforementioned contradictory reports on the clinical effects of hormones on dyskinesia (B~dard et al., 1977; 1979; Villeneuve et al., 1980; Koller et al., 1982; Barber et al., 1976; Nausieda et al., 1979a). REFERENCES BARBER, P. V., ARNOLD, A. G. • EVANS, G. 0976) Recurrent hormone-depending chorea: effects of estrogens and progesterone. Clin. Endocr. 5, 291 - 2 9 3 . BI~DARD, P. J., LANGELIER, P. & VILLENEUVE, A. (1977) Estrogens and the extrapyramidal system. Lancet ii, 1367 - 1368. BI~DARD, P. J., DANKOVA, J., BOUCHER, R. & LANGELIER, P. (1978) Effect of estrogens on apomorphineinduced circling behavior in the rat. Can. J. Physiok Pharmac. 56, 538 - 541. BI~DARD, P. J., LANGEL1ER, P., DANKOVA, J., V1LLENEUVE, A., Dl PAOLO, T., BARDEN, N., LABRIE, F., BOISSIER, J. R. ~¢ EUVRARD, C. (1979) Estrogens, progesterone, and the extrapyramidal system. Adv. NeuroL 24, 411 - 422.
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