Pharmacological Studies of Ergometrine And

Pharrnaco/ogical Research Communications, Vol. 9, Ho, 3, 1977 299

BROMOCRIPTIN AND METHYLERGOMETRINE: PHARMACOLOGICAL APPROACH OF THE MECHANISM OF THEIR CENTRAL EFFECTS

Alain J. PUECH, Pierre SIMON, Raymond CHERMAT and Jacques-R. BOISSIER D6partement de Pharmacologie, Facult~ de M6decine Piti~-Salp~tri~re, 91 Bd. de l'H~pital - F75634 Paris C~dex 13. and Unit~ de Recherche de Neuropsychopharmacologie de I'INSERM, 2 rue d'Al~sia - F75014 Paris. Received 8 March 1976 SUMMARY Bromocriptin and methylergometrine were studied with a battery of classical tests used in psychopharmacology. Both drugs have the typical profile of the dopaminergic stimulant drugs. Stereotyped behavior induced by both drugs were studied after various pharmacological pretreatments. Results of these interactions are in favor of a direct stimulation of dopaminergic receptors by both drugs. Since some characteristics of stereotyped behavior induced by bromocriptin are suppressed by methysergide but not by fenclonine, bromocriptin could also be a direct stimulant of serotoninergic receptors.

INTRODUCTION • i m - -- Experimental and clinical data suggest that some ergot derivatives are central dopaminergic stimulant drugs. Ergometrine and dopaminergic stimulants induce circling behavior in rats with unilateral 6-OH-dopamine-induced degeneration of the nigrostriatal dopamine pathway (Woodruff et al., 1974). Administered bilaterally in nuclei acumbens, ergometrine like dopamine increases locomotor activity in rats (Pijnenburg et al., 1973 ). Bromocriptin induces stereotyped behavior in rats (Johnson and al., 1973), circling behavior in rats with unilateral 6-OH-dopamine-induced degeneration of the nigrostriatal dopamine pathway (Corrodi and al., 300 Pharmacological Research Communications, VoL 9, No. 3, 1977

1973 ; dohnson and al.. 1973) and hvDothermia in mice (Calne and Claveria, 1975) ; it antagonises neuroleptic-induced catalepsy in mice (Jonnson ana al., 1973} and surgically-induced tremor in monkeys (Miyamoto ~nd al., 1974). Bromocriptin decreases dopamine turnover in rats (Corrodi and al., 1974 ; Fuxe and al., 1974) and decreases prolactin secretion in different animal species (Pasteels and al., 1971). In humans, bromocriptin decreases.prolactin secretion (Del Pozo and al., 1972) and was found to have a potent therapeutic effect in parkinsonian patients (Calne and al., 1974). We present here the effects of bromocriptin and methylergometrine in the experimental conditions that were previously used in our laboratory for the determination of the central effects of five dopaminergic stimulant dr ugs/(Puech et al., 1975).

METHODS Male Swiss mice weighing 18-22 g and male Wistar AF rats (Evic Ceba) weighing 200-220 g were used. Methylergometrine was used in aqueous solution, bromocriptin after suspensio~ with acacia gum. Stereotyped behavior was appreciated for each rat, from 0 to 3, every 10 minutes until, its disappearance (Simon et Chermat, 1972). For this appreciation, rats were individually placed in plexiglass boxes (20 x 10 x 10 cm) immediately after i.p. injections of the drug. Locomotor activity in mice was measured using photocell actimeter described by Boissier and Simon (1965). Rectal temperature in mice was measured with a heat sensitive the~mi ster probe. For reserpine interaction, drugs were administered 4 hours after reserpine (2.5 mg.kg'1). Recta] temperature and palpebral ptosis, rated from O~to 4, were appreciated in mice. Catalepsy induced by prochlorperazine (12 mg.kg"1 i.p.) was appreciated by the homolateral crossing legs test (Boissier et Simon, 1963). Toxicity in aggregated mice was appreciated by comparison of toxicity between mice placed, either individua]]y or in groups of 10, in a plexiglass box (20 x 10 x 10 cm). Phar~nacological Research Communications, Vol. 9, No. 3, 1977 301

RESULTS St.ereo.typed behavior in rats. Bromocriptin and ~.ethylergometrine induced stereotyped behavior in rats (fig. 1). However, there are differences between the two drugs. Methylergometrine induced stereotyped behavior in all rats ; this behavior appeared rapidly and lasted less than 2 hours. Bromocriptin-induced stereotyped behavior started after 2 hours, for an approximate duration of 12 hours. Some animals never showed stereotyped behavior whatever the dosage, and for the others the intensity of stereotyped behavior could vary from one time to another.

~ 3 r- ME THYLERGOMETRINE BROMOCRIPTIN

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~,-,I f ~ ,-,._.-_.-,J" .~ U.-L..,....I~.~.~ ~ w i ,l,--,w_ ! ,- I ,I , !_ _ I 0 1 20 1- 3 4 5 6 7 hours Fig. I Stereotyped behavior in rats. Cotations from 0 to 3. 6 rats minimum for each group. Figures on the curves indicate dosage (mg.kg-1 i.p.).

Pretreatment of the rats with ~C-methylparatyrosine ( ~4 roT), reserpine, a( mT + reserpine or parachlorophenylalanine (fenclonine) failed to modify methylergometrine-induced stereotyped behavior (Table I). Bromocriptin-induced stereotyped behavior was decreased by ~(mT or fenclonine pretreatment. Pretreatment by reserpine, alone or in combination with ~mT, clearly potentiated bromocriptin-induced stereotypecl behavior : the kinetics were not modified but all animals presented an intense and constant stereotyped behavior for many hours, After methysergide pretreatment, stereotyped behavior was potentiated and - what see~s more significant - occured more rapidly, 302 Pharmacological-Research Communications, Vol. 9, No. 3, 1977

Table I

In.teraction_of pharmacological agents with_ bromocriptin_=_+- _" or_ methyl: ergometrine-induced~stereotyped behavior in rats. Results are expressed in percent of controls. This percentage was calculated from the indexes of stereotyped behavior appreciated every 10 minutes until disappearance.

mg. kg -1 time (h) bromocriptin methylergometrine be fore 64 mg.kg-I i .p. 8 mg.kg-1 i .p. i .p. drug saline I00 i00 ~( -methyl tyrosine 64 2.5 63 97 reserpine 4 18 301 86 reserpine 4 18 + 283 94 o< mT 64 2,5 fenc lonine 128x3 48,24,1 43 methysergide 64 0.5 161

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Fig. 2 Locomotor activity in mice. ------mm t -- _ _ Motor activity was measured during 30 min., mice being placed in the actimeter only at the beginning of the measurement (30 rain. after i,p, injection of methylergometrine or 60 rain, after bromocriptin). 10 animals minimum for each group. Blackened data points indicate a significant difference (p~ 0.05) from controls. Pharmacological Research Communications, VoL 9, No. 3, 1977 303

Locomotor activity in mice. With increasing doses, the effects of the two drugs on locomotor activity were biphasic : decrease, then increase (fig. 2).

Rectal temperature in mice. Both drugs clearly decreased rectal temperature in mice (fig. 3). However, with methylergometrine, there was no hypothermia at the highest dose used. Reserpine antagonism. Methylergometrine,.but not bromocriptin, antagonised reserpine-induced hypothermia and palpebral ptosis (fig.4).

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ca ~, ,c3 BROIg(ORIPTIN % e: 33. o 0~006 0.25 I 4 16 64 roB. k9" i.F Fig. 3 Rectal temperature in mice. Results given in this figure are those observed at the peak effect : 30 min. after methylergometrine and 60 min. after bromocriptin. 6 mice minimum for each group. Blackened data points indicate a significant difference (p C O.05)from control~

Antagonism of. neuroleptic-induced_catalepsy. Both drugs clearly antagonised prochlorperazine-induced catalepsy in rats (fig. 5).

Toxicity in aggrega.ted mice. The toxicity of methylergometrine was greater in aggregated mice than in isolated animals : with isolated mice, the number of deaths after 16, 32, 64 and 128 mg.kg-1 was respectively O, 03 I and 2 out of 10. With aggregated mice, the number of deaths after 2, 4, 8, 16 and 32 mg.kg"I was respectively O, 1, 3, 10 and 10 out of 10. With the doses of bromocriptin used (64, 128 and 256 mg.kg"1) there was no mortality either in isolated or in aggregated mice. 304 Pharmacological Research Communications, VoL 9, No. 3, 1977

I~r"~ METHYLERGOME" - "- -'--- " .... TRINE -- n~nI. BROM OCRi PTINI" f=~ ...... _ _ ", ...... /''01 Oi /.0/"

31L :: 0.5 1 2 4 8 16 "" 64 rag. k9" i.p. Fig. 4 Interaction with reserpine in mice. : - --_ _-- -- ,,-, i i Methylergometrine or bromocriptin were administered 4 hours after reserpine 2.5 mg. kg I i.p. The effects indicated here were recorded i hour after the drug administration (peak effect). 6 mice minimum for each group.

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J., I I I t m 0.25 0.5 1 2 4 8 16 32 64 128 :3 Z rag. kg" i@. Fig. 5 !nteraction_wi_thprochlo.rperazine-in.d_uced cataleps ~ in rats, Methylergometrine and bromocriptin were administered 4 hours after prochlorperazine (8 mg.kg-l). 6 rats minimum for each group.

DISCUSSION m While studying five central dopaminergic stimulant drugs (apomorphine, dexamphetamine, L-DOPA + carbidopa, amantadine, piribedil) with the same methodology, we found various common effects (Puech et al., 1975) : Pharmacological Research Communications, Vol. 9, No. 3, 1977 305

- increase of the reactivity to external stimuli ; - biphasic effect on motor activity : i.e., decrease and, with higher doses, increase (except for amantadine) ; - hypothermia ;

- antagonism of neuroleptic-induced catalepsy ; - apomorphine, L-DOPA + carbidopa and, more clearly, dexamphetamine, but not the two other drugs, antagonised reserpine- induced ptosis and hypothermia. The profile of methylergometrine is very similar to that of dexamphetamine : in addition to the above common effects, both-'drugs are more toxic in aggregated than in isolated mice, have a biphasic effect on rectal temperature, and clearly antagonise reserpine-induced ptosis and hypothermi a. However, contrary to dexamphetamine, stereotyped behavior induced by methylergometrine was not modified by ~ mT or reserpine or ~ mT + reserpine pretreatment. These results suggest a direct action. The profile of bromocriptin is very similar to that of apomorphine or of L-DOPA + carbidopa. However., the kinetics of bromocriptin effects are rather peculiar : long latency of action, long duration, intensity of effect varying from one moment to another. The mechanism of bromocriptin-induced effect is far from being clear. After reserpine + o( mT pretreatment, bromocriptin-induced stereotyped behavior was clearly increased ; thus, stimulation of dopaminergic receptors by bromocriptin is probably direct, and the potentiation observed could be explained by dopaminergic receptors supersensitivity, as it has been proposed for apomorphine (Tarsy and Baldessarini, 1974). The circling behavior towards the innervated side in rats with unilateral 6-OH-dopamine-induced degeneration of the nigrostriatal dopamine pathway, and the decrease of central dopamine turnover observed after bromocriptin (Corrodi et al., 1973), are in keeping with this hypothesis. After o< mT, bromocriptin-induced stereotyped behavior is slightly decreased. However, this decrease could probably be explained by a non-specific antagonism : the e( roT-induced sedation could be strong enough to explain the observed decrease regarding the low intensity of the bromocriptin-induced stereotyped behavior. Bromocriptin-induced stereotyped behavior is different from the stereotyped behavior induced by other dopaminergic stimulants in three 306 Pharmacological Research Communications, VoL 9, No. 3, 1977

ways : long latency, change in intensi~y in the same rat from one moment to another, . resistan ce~i of some animals. After methysergide pretreatment, the decrease and even suppression of these characteristics suggest the hypothesis of their relation to a serotoninergic stimulation by bromocriptin, which could modulate the result of the dopaminergic stimulation by this drug. The serotoninergic stimulation is probably a direct one, because of the lack of changes after pCPA pretreatment. This hypothesis is reinforced because stereotyped behavior induced by amphetamine - a stimulant of both dopaminergic and serotoninergic systems - is potentiated-by methysergide, whereas stereotyped behavior induced by apomorphine - a specific stimulant of dopamine receptors - is not (Simon et al., 1975).

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