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16 mars 2006
Eur J Pharmacol
2002; 447; 1; 109-114 
Carmoxirole is able to reduce amisulpride-induced hyperprolactinemia without affecting its central effect
Marchese G, Ruiu S, Casti P, Bartholini F, Saba P, Gessa GL, Pani L
Neuroscienze, Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Prolactin blood level and apomorphine-induced yawning were studied in rats treated with the substituted benzamide amisulpride in association with bromocriptine or carmoxirole; two dopamine D(2) receptor agonists with high or low propensity to cross the brain-blood barrier, respectively. Administration of amisulpride produced a maximum increase in rat serum prolactin level (315+/-18%) vs. vehicle-treated animals (ED(50)=0.25+/-0.017 mg/kg, s.c.). The concurrent administration of carmoxirole or bromocriptine completely reversed the hyperprolactinemia induced by amisulpride (0.5 mg/kg, s.c.) (ID(50)=14.9+/-0.8 mg/kg and 0.81+/-0.03 mg/kg, respectively). Carmoxirole (15 mg/kg, i.p.) did not affect yawning induced by apomorphine (0.08 mg/kg, s.c.) nor amisulpride (0.5 mg/kg, s.c.) blockade of apomorphine-induced yawning. Conversely, a significant increase in the number of yawns was observed when bromocriptine (0.8 mg/kg, i.p.) was associated with apomorphine in the absence or presence of amisulpride. These results suggested that a peripheral dopamine D(2) receptor agonists could be a useful tool in alleviating amisulpride-induced hyperprolactinemia without possibly affecting its central effect.
1. Introduction
The finding that low doses of amisuipride, an atypical antipsychotic of the substituted benzamides class, improved negative symptoms of schizophrenia (Boyer et al., 1995) led to the hypothesis that, at small doses, this drug could be useful in depressive symptoms (Puech et al., 1981). On such basis, amisulpride has been largely and successfully employed in dysthymia and major depression (Lecrubier et al., 1997; Smeraldi, 1998; Ravizza, 1999). This therapeutic property of amisulpride has been associated to its selective antagonism for dopamine D2 and D3 autoreceptors (Perrault et al., 1997). Indeed, as it has been amply demonstrated, the dopamine D2-like autoreceptors are involved
in the inhibition of dopamine release, neuronal firing and tyrosine hydroxylase activation (Lejeune and Millan, 1995; Saud Chagny et al., 1991; Walters and Roth, 1976). The selective antagonism of these autoreceptors by low doses of amisulpride should then produce an increase in the dopaminergic neurons firing (Di Giovanni et al., 1998) and release (Shoemaker et al., 1997) in the limbic system, which are accounted for the antidepressant properties of the drug. In line with this hypothesis, different studies conducted on laboratory animals indicated that low doses of amisulpride selectively block dopamine D2 autoreceptor in vivo. For instance, very low doses of amisulpride (0.2-0.3 mg/kg) were able to antagonize rat yawning and hypomotility induced by pre-synaptic doses of apomorphine, while only very high doses of amisuipride (30-100 mg/kg) are needed to reduce rat hypermotility and stereotypies induced by post-synaptic doses of apomorphine (Perrault et al., 1997; Shoemaker et al., 1997).
Although these studies showed that amisulpride displays a pre-synaptic selectivity, clinical studies on healthy volunteers demonstrated that, even at small doses, amisulpride increases prolactin blood level (Wetzel et al., 1994), indicating that the same doses of amisuipride which antagonize mesolimbic dopamine autoreceptors are able, outside the brain-blood barrier, to block pituitary dopamine D2 postsynaptic receptors producing hyperprolactinemia as a side effect.
The presence of dopamine D2 receptor in the anterior and intermediate lobes of the pituitary gland has been extensively demonstrated with biochemical and pharmacological techniques (Enjalbert and Bockaert, 1983; Memo et al., 1986) and the gene encoding for both the dopamine D25 and D2L receptor isoforms has been later found in pituitary lactotroph cells (Dal Toso et al., 1989; Meador-Woodruff et al., 1989; Bunzow et al., 1988). The stimulation of pituitary dopamine D2 receptor by dopamine released from tuberoinfundibular neurons was proven to reduce prolactin secretion from the pituitary gland, as confirmed by cell culture studies on lactotroph cells and by in vivo evidence (Burns et al., 1991; Ben-Jonathan, 1985). The block of pituitary dopamine D2 receptors by amisulpride should then reduce the dopaminergic inhibition of the pro lactin release, leading to hyperprolactinemia in patients (Wetzel et al., 1994).
The hyperprolactinemia due to different pathological status is currently treated by stimulating pituitary dopamine D2 receptor with dopamine D2 receptor agonists, such as bromocriptine, that are among the most effective drugs able to normalize plasma prolactin levels (Pinzone et al., 2000).
An attempt to reduce the increase in prolactin secretion induced by benzamides class of compounds with the use of dopamine D2 receptors agonists was carried out. For instance, bromocriptine was administered to rat treated with the benzamide derivative sulpiride (Hofmann et al., 1979). However, since bromocriptine readily crosses the brainblood barrier, it lowered sulpiride-induced hyperprolactinemia, but it also suppressed the 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation induced by sulpiride in the nucleus accumbens, thus interfering with the sulpirideinduced increase in dopamine synthesis which is thought to be at the basis of its action as an antidepressant (Tagliamonte et al., 1975).
Recently, a new dopamine D2 receptor agonist carmoxirole has been synthesized (Haase et al., 1991). Carmoxirole was proven to reduce basal prolactin blood levels in naive rat and showed low propensity to cross the blood-brain barrier, since it exerted no effect on striatal L-DOPA accumulation up to the dose of 100 mg/kg and it was able to affect the central levels of biogenic amine only at high doses (Haase et al., 1991).
In the present paper, we evaluated the possibility that carmoxirole may reverse the amisulpride-induced hyperprolactinemia without affecting the central effect of this substituted benzamide. For this purpose, we compared the effect of carmoxirole and bromocriptine on prolactin blood level and on apomorphine-induced yawning in rats acutely treated with low doses of amisulpride.
4. Discussion
When used in small doses (50-100 mg) the benzamide derivative amisulpride possesses an antidepressant effect (Lecrubier et al., 1997; Ravizza, 1999) and this drug is successfully used, at these doses, in the treatment of negative symptoms of schizophrenia and of dysthymia. However, like other substituted benzamides, even low doses of amisulpride elevate plasma prolactin levels in patients, posing the risk of low compliance (Wetzel et al., 1994; Von Bahr et al., 1991).
In the present work, using the rat as an animal model, we confirmed the high propensity of very small doses of amisulpride to induce hyperprolactinemia. Furthermore, consistently with other studies (Scatton et al., 1997; Perrault et al., 1997), we found that amisulpride (0.5 mg/kg) was able to completely reverse apomorphine-induced rat yawning.
Although some pharmacological or anatomo-physiological controversies exist concerning the different brain region involved (Argiolas and Meus, 1998), the apomorphineinduced yawning is generally considered as a centrally mediated effect due to a direct stimulation of the dopamine D2 receptor. In our condition the same doses of amisuipride that were able to antagonize this behavioral effect of apomorphine produced a maximal increase in prolactin
blood level. Indeed, similarly to what has been reported in humans (Wetzel et al., 1994), in the rat we found a doserelated association between the hyperprolactinemia induced by amisulpride and the central effect mediated by the benzamide (i.e. the antidepressant effect in humans and the antagonism of apomorphine-mediated yawning in rats).
The present results indicate that low doses of bromocriptine decreased amisulpride-induced hyperprolactinemia, but they also reduced the effect of amisulpride on apomorphine-induced yawning. On the other hand, the peripheral dopamine D2 agonist carmoxirole was able to reduce the amisulpride-induced hyperprolactinemia at doses much higher than bromocriptine, but without affecting the amisulpride ability to reduce apomorphine-induced yawning.
The different effect of the two dopamine D2 receptor agonists on amisulpride-induced hyperprolactinemia reflects their different affinity for the pituitary dopamine D2 receptors, as observed in our binding study. On the other side, the lower propensity of carmoxirole to cross the brain-blood barrier may explain the different effect, with respect to bromocriptine, on amisuipride-induced central effect. Bromocriptine at low doses is able to reduce cocaine-induced hypermotility and is known to alter dopamine synthesis and release in naive rats (Brannan et al., 1993; Jackson et al., 1995). On the other hand, carmoxirole (10-100 mg/kg, s.c.) exerts no effect on hypothalamic L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation and produces only a small reduction of striatal DOPAC and homovanillic acid (HVA) levels, suggesting that carmoxirole is devoid of central effect at such doses (Haase et al., 1991). Consistent with this possibility, we found that carmoxirole did not affect spontaneous locomotor activity up to the dose of 60 mg/kg.
Interestingly, bromocriptine affected the apomorphine and apomorphine plus amisulpride effect on yawning at a dose devoid per se of any behavioral effects. A peculiarity that was also observed using apomorphine to antagonize cocaine behavioral arousal (Campbell et al., 1989). It is possible that the reported in vivo slow dissociation of bromocriptine from the dopamine receptor may account for an over-effect of the drug when in the presence of a dopamine receptor stimulation or antagonism (Bannon et al., 1980). In any case, this property of bromocriptine is not in favor of any possible use in reducing hyperprolactinemia induced by amisulpride in depressive patients, in spite of its widespread clinical use as an anti-hyperprolactinemia agent (Pinzone et al., 2000).
In conclusion, our result indicated that, even in very small doses, amisuipride is able to produce hyperprolactinemia and to reverse centrally mediated apomorphineinduced yawning in rats. The comparison of the effects of carmoxirole and bromocriptine on amisulpride-induced hyperprolactinemia and yawning indicated that only carmoxirole was able to restore normal prolactin blood level without affecting the central activity of amisulpride in rats. These results might suggest that, in humans, the combination of carmoxirole and amisulpride may leave intact the central effect of this benzamide, which is relevant for its therapeutic response in affective and cognitive symptoms of dysthymia and negative symptoms of schizophrenia, while antagonizing the endocrine peripheral effect of amisulpride. However, further studies will be needed in order to evaluate the other actions of carmoxirole in the periphery (such as those on blood vessels, kidney, etc.) and particularly when given in combination with a substituted benzamide.