Biphasic effect of estradiol and domperidone on lingual dyskinesia in monkeys

EXPERIMENTAL

NEUROLOGY

82, 172-182 (1983)

Biphasic Effect of Estradiol and Domperidone Lingual Dyskinesia in Monkeys PAULB~DARD,REN~BOUCHER,TH~R&E ANDFERNANDLABRIE] Department of Anatomy, Molecular Endocrinology, Received

Faculty of Medecine, Le Centre Hospitalier October

on

DI PAOLO,

Lava1 University and *Department of de Wniversiti Laval, Qukbec. Canada

8. 1982: revision

received

May

4, 1983

In previous work, we demonstrated in animals and humans an antidopaminergic effect of estradiol at the level of the striatum. In the present study, we tested the effect of a large dose of estradiol (0.5 mg s.c.) administered either acutely or during several days in four female ovariectomized monkeys, displaying a persistent buccolingual dyskinesia due primarily to a midbrain lesion, but which is markedly enhanced by dopaminergic agonists. One of the monkeys also displayed a lesion-induced parkinsonian-like tremor of the opposite limbs. Chronic administration of estradiol markedly reduced the apomorphine-induced potentiation of the dyskinesia but did not affect the tremor. A single dose of estradiol was followed after 24 h by a 75% reduction of the effect of apomorphine on the dyskinesia but a 50% increase in the response to apomorphine was seen after 2 weeks. The response was at the control level after 30 days. Domperidone, a peripheral dopamine agonist that does not cross the bloodbrain barrier and which causes an elevation of prolactin similar to that seen after estradiol, is followed by a similar biphasic modification of the response to apomorphine. Our results suggest that estradiol may have opposite effects on the sensitivity of the striatal dopamine receptors and therefore on dyskinesia, depending on the time of observation. An elevation of prolactin appears to have similar effects.Moreover, some effects of these hormones may be delayed by several days to weeks in primates.

INTRODUCTION There is now ample biochemical evidence that estrogens affect dopaminergic transmission in the nigrostriatal dopaminergic system (14, 15, 19, 20, 22, Abbreviation: DA-dopamine. ’ This work was supported by the Medical Research Council of Canada and the Fonds de la Recherche en Sante du QuCbec. Professor Bedard and Mr. Boucher are in the Dept. of Anatomy and Dr. Di Paolo and Dr. Labrie in the Dept. of Molecular Endocrinology. 172 0014-4886/83 $3.00

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24). In animal behavioral models of striatal dopaminergic activity, several authors reported results consistent with antidopaminergic properties of estrogens (3, 5, 7, 11, 16, 19-21). Others, however, observed increased stereotypies induced by dopaminergic agents in rodents pretreated with estrogens (12, 23, 29) which suggests facilitation of dopaminergic transmission. The same discrepancy is observed in clinical reports. Estrogens can under certain circumstances reduce tardive dyskinesia (7, 8, 27, 36) and dopainduced dyskinesia is parkinsonian patients (7, 8, 27). It is known, however, that contraceptive drugs containing estrogens can sometimes induce chorea in susceptible women (2, 10, 30). Thus, although research indicates that estrogens affect nigrostriatal dopaminergic activity, their effects on dyskinesia are not clear (2, 7, 8, 10, 27, 36). The purpose of our study was to assess the effects of estradiol on buccolingual dyskinesia induced in female monkeys by a midbrain lesion. The lesion was made for the purpose of inducing a parkinsonian-like tremor in the contralateral limbs. As described elsewhere (31, 32) the lesion-induced tremor in monkeys may be due to effects on several structures including the pars compacta of the substantia nigra, the red nucleus, the superior cerebellar peduncle, and the central tegmental tract. The dyskinesia which was a coincidental finding in monkeys with such lesions, involves tongue rolling and twisting in the mouth, as well as tongue protrusion in a manner very similar to what is observed in patients with neuroleptic-induced dyskinesia or in some parkinsonian patients with dopainduced dyskinesia. In our experience, Macacca fascicularis appear more susceptible to such dyskinesia than M. mulatta. The dyskinesia is present spontaneously but markedly enhanced by dopaminergic agents whereas the tremor is suppressed by the same agents, making it possible to study at the same time the effect of hormones on a model of the therapeutic effect as well as one of the main side effects of L-dopa in Parkinson’s disease. MATERIAL

AND

METHODS

Twelve female M. fascicufaris underwent a left electrolytic lesion of the midbrain under ketamine anesthesia. The lesion was made stereotaxically according to coordinates A 8.2, L 1.5, V - 1. The five animals which developed a dyskinesia were subsequently ovariectomized under ketamine anesthesia. The experiments reported here were conducted at least 6 months after the midbrain lesion. Recording of Tremor and Dyskinesia

All observations and recordings were made with the animals sitting in a chair and by the same observer, between 1300 and 1700 h. The tremor was

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FIG. 1. Photomicrograph of transverse section through the caudal diencephalon and mesencephalon of a monkey with lingual dyskinesia, showing extensive destruction by the lesion (L) of the left parafascicular nucleus (pfc) and fasciculus retroflexus (FR) with resulting cell loss in the ipsilateral habenula (Hb). Note sparing of substantia nigra (SNC). The red nucleus (RN), superior cerebellar peduncle. and central tegmental tract were partially

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FIG. 2. Tremor suppression in minutes by three doses of apomorphine (0.0 1, 0.02, 0.04 mgl kg, s.c.) before and during (shaded bars) daily treatment with estradiol benzoate (0.5 mg s.c.). Each bar represents thk mean f SE of at least three experiments in the same animal,

recorded electromyographically in antagonistic muscles of the forearm. In most experiments we recorded the tremor suppression time in minutes after apomorphine (0.01 to 0.04 mg/kg, s.c.). The dyskinesia was confined to the buccolingual sphere. It was assessed with a time-event counter (built by Ontario Crippled Children Center). An observer (always the same) pressed a button each time the monkey’s tongue protruded beyond the line of the teeth and for as long as the tongue was in this unnatural position. At the end of the experimental period we therefore had a count of the number of tongue protrusions as well as of the total duration of the dyskinesia in seconds. This last parameter was used for the calculations. Drugs

The following drugs were used: apomorphine hydrochloride (a dopamine agonist, Smith, Kline and French), 0.01 to 0.04 mg/kg S.C. in saline; domperidone (a peripherally acting dopamine antagonist), 1 mg/kg i.m. in saline plus acetic acid (Janssen); estradiol benzoate (Sigma), 0.5 mg S.C. in oil. Testing Schedules

In the first experiment, the only monkey displaying both the tremor and the lingual dyskinesia was tested repeatedly with apomorphine, 0.01, 0.02, 0.04 mg/kg S.C. during a period of 3 weeks. The same procedure was then repeated during a similar period when the animal was receiving estradiol benzoate, 0.5 mg S.C. daily. In a second series of experiments we used four monkeys with a lesion displaying dyskinesia, only one of which had tremor, and measured the potentiating effect on the dyskinesia of a single dose of apomorphine, 0.02

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mg/kg S.C. before and at various intervals, after a single dose (0.5 mg) of estradiol benzoate (24 h, 72 h, 6 days, 14 days, 30 days). After a drug-free period of several weeks the same procedure was applied but the animals received, instead of estradiol, domperidone, 1 mg/kg i.m. They were tested with apomorphine, 0.02 mg/kg S.C. before and 4 h, 24 h, 6 days, and 14 days after domperidone. Two other ovariectomized female monkeys with similar brain stem lesions were anesthetized at 0900 and a catheter was placed in a vein of their hind limbs. They received an injection of estradiol benzoate, 0.5 mg S.C. in oil or domperidone, 1 mg/kg i.m., at 1100 h. Blood samples were drawn hourly from 1000 to 1800 and then at 1100 and 1200 the next morning. This experiment was carried out in anesthetized animals to avoid stress-induced elevations of prolactin. The blood was centrifuged and the serum frozen for prolactin assay using a radioimmunoassay for primate prolactin (25). RESULTS Efect of the Lesion Of the 12 monkeys which underwent surgery, only one developed after several months a contralateral postural tremor which has now been present for more than 4 years. Five, however, were noticed in the days following recovery from surgery to have a spontaneous buccolingual dyskinesia which has now been present for at least 2 years. One of those animals (not displaying tremor) died during a pharmacological experiment. The brain was removed, fixed in 10% Formalin, and stained with basic fuchsin and fast blue. Histological analysis revealed that the lesion did not involve the midbrain structures usually associated with tremor production; in fact it completely spared the substantia nigra. Rather, it was placed in the left parafascicular nucleus which was completely destroyed. The fasciculus retroflexus was also heavily damaged resulting in a marked cell loss in the ipsilateral habenula (Fig. 1). Efect of Apomorphine,

Estradiol,

and Domperidone

When administered repeatedly to the same trembling monkey, apomorphine was found to suppress the tremor in a dose-dependent manner for periods varying between 15 and 45 min (Fig. 2). Chronic treatment with estradiol did not modify the efficacy of apomorphine in suppressing the tremor. Before estradiol, the dyskinesia was markedly increased by apomorphine also in a dose-dependent manner as shown in Fig. 3 where it is expressed in cumulative dyskinesia time in seconds between 15 and 30 min after apo-

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FIG. 3. Lingual dyskinesia expressed in seconds obtained from cumulative count on a timeevent counter during I5 min (from the 15th to the 30th min) after three doses of apomorphine 0.01, 0.02, and 0.04 mg/kg, KC., before and during (shaded bars) daily treatment with estradiol benzoate 0.5 mg, S.C.Each bar represents the mean t SE of at least three experiments in the same animal. *P < 0.01 Student’s t test.

morphine. Estradiol treatment markedly and significantly decreased the potency of apomorphine in enhancing the dyskinesia. In the second experiment, the intermediate dose (0.02 mg/kg s.c.) of apomorphine was used. As shown in Fig. 4, one single dose of estradiol(0.5 mg s.c.) resulted after 24 h in a significant (75%) reduction of the total dyskinesia % 200

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FIG. 4. Lingual dyskinesia measured in seconds (with time-event counter) 15 min before and 60 min after apomorphine 0.02 mg/kg, S.C.Each bar is the mean dyskinesia-time of four monkeys, expressed in percentage of the control value (0). The dyskinesia was measured before and at various intervals after an injection of estradiol benzoate (Eb). *P < 0.05 paired t test.

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time (in seconds) recorded 15 min before and 1 h after the apomorphine injection for a total of 75 min. The efficacy of apomorphine had recovered after 72 h but there was a 50% increase in the apomorphine-induced dyskinesia after 14 days which disappeared by the 30th day after the estradiol injection. In the anesthetized monkeys, estradiol caused a rapid elevation of prolactin, maximal at 60 rig/ml plasma 2 h after the injection and lasting 5 h. Domperidone caused a greater stimulation of prolactin secretion to as much as 200 rig/ml plasma, maximal at 4 h and lasting 7 h. After domperidone (1 mg/kg, Fig. 5), there was no significant reduction in the apomorphine effect on the dyskinesia at 4 h corresponding to the maximum elevation of the prolactin concentration and therefore comparable to marked blockade of the pituitary dopamine receptors (28, 34). At 24 h, when the prolactin concentration was at the control value, there was a 50% reduction in the effect of apomorphine, which, however, due to the small number of animals, was not significant. On the other hand, at 6 days, the

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FIG. 5. Lingual dyskinesia measured in seconds (with a time-event counter) 15 min before and 60 min after apomorphine 0.02 mg/kg, S.C.Each bar is the mean dyskinesia count obtained in four monkeys expressed in percentage of the control value (C), 4 h (D), 24 h, 6 days, and 14 days after an injection of domperidone 1 mg/kg, i.m. *P < 0.05 paired f test.

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response to apomorphine was markedly and significantly of control) but returned to the control value at 14 days.

179 increased (225%

DISCUSSION Our results demonstrate that estradiol, administered either chronically or in a single dose of 0.5 mg, can antagonize the apomorphine-induced potentiation of lingual dyskinesia in monkeys. This effect of apomorphine may be presumed to be dopaminergic in nature and exerted at the level of the striatum although the precise site is not yet determined. The antidopaminergic effect of estradiol is in agreement with earlier observations in rats (3, 5, 7, 19-21) as well as on the dyskinesia in humans (7, 8, 27, 36). It apparently involves the dopaminergic nigrostriatal systems as one can observe changes in dopamine (DA) receptor binding (14, 15, 17, 24) in the striatum as well as changes in DA concentrations ( 18) after estradiol treatment. Changes in acetylcholine turnover appear to be secondary to this effect on DA receptors (19, 20). Estradiol, on the other hand, did not modify the antitremor effect of apomorphine although the latter appeared to be dose-dependent. A tentative explanation of this observation would be that tremor suppression is an allor-none phenomenon that occurs at a given threshold of stimulation (or inhibition) and persists for as long as the stimulation (or inhibition) is above threshold. It would thus be dependent on the dose of apomorphine and the speed of elimination. This could therefore suggest that the metabolism of apomorphine is not affected by estradiol (11) and that although the top of the curve of the apomorphine effect may be blunted (decreased maximum effect) as seen on the dyskinesia, the base remained unchanged. The alternate explanation supported by some of our earlier clinical results (9) would be that tremor suppression and dyskinesia depend on two different dopamine receptors (13). That would make it possible to separate in parkinsonian patients some of the therapeutic effects of dopamine agonists from the main side effect. The effect of a single dose of estradiol on the potency of apomorphine is biphasic. At 24 h, there is a marked inhibition but after several days to weeks one observes a facilitation. The same phenomenon was observed in rats by Gordon (21) and Joyce et al. (26). This dual effect might be explained by several mechanisms such as (i) rebound after blockade, (ii) sequential effect of estradiol on two different DA receptors having opposite actions (13), (iii) sequential effect of estradiol on two neurotransmitters having opposite actions, (iv) transformation of estadiol into a metabolite with an opposite action, and (v) apart from its own action on striatal dopamine mechanism, estradiol could release or block the release of other substances with different actions which would act later.

180

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AL.

Interestingly, a similar sequence of inhibition followed by supersensitivity to apomorphine was seen after haploperidol in mice (35). That report together with the similar effect on striatal dopamine receptors supports our earlier claim that estradiol may be viewed under certain conditions as a weak neuroleptic (6). Some of the behavioral, biochemical, as well as electrophysiologic effects of estradiol appear to be suppressed by hypophysectomy (1, 19, 20,24). This suggests that part or all of the estradiol effect is mediated through the pituitary. One of the effects of estradiol at the level of the pituitary is to increase prolactin by a direct antidopamine action (33). Prolactin can itself affect the activity of striatal DA receptors (34). In the experiment reported here, we sought to elevate prolactin by an alternate compound which would be without direct action by itself on the striatal DA receptors. We chose domperidone, a potent DA antagonist which does not cross the blood-brain barrier in low doses (37). Domperidone caused a higher and more prolonged elevation of prolactin than estradiol but at the time of maximal elevation of prolactin, there was no modification of the apomorphine-induced dyskinesia. After that, however, we observed roughly the same response pattern as after estradiol with a slightly different time course, that is, a reduced response to apomorphine at 24 h followed by a marked facilitation at 6 days and a return to baseline at 14 days. Although we cannot be certain that this effect of domperidone is mediated through the elevation of prolactin, this observation suggests that some effects of estradiol are mediated through prolactin or alternatively that estradiol and prolactin have similar but independent actions on dopamine receptor sensitivity. The latter possibility is reinforced by recent observations by DiPaolo et al. (17) which show that in ovariectomized and hypophysectomized rats, both estradiol and prolactin can increase [3H]spiroperidol binding to about the same extent in striatal tissue. We therefore conclude that extradiol and prolactin have similar, but independent biphasic effects on striatal postsynaptic DA receptor sensitivity with a time course similar to a neuroleptic. Our results also suggest that if one is looking for facilitation of the action of dopaminergic agents by drugs that elevate prolactin in parkinsonian patients, one should examine the patients for several days. It becomes more and more evident that the hormonal status of animals or patients has to be taken into account when one is considering the effect of drugs which affect the nigrostriatal dopaminergic system. REFERENCES 1. ARNAULT,

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