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mise à jour du
1 mars 2009
J Neural Transm
Some central pharmacological effects
of the calcium channel antagonist flunarizine
 A. Czyrak, E. Mogiinicka, and J. Maj
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland


Our earlier studies showed that dihydropyridine calcium channel antagonists have some central pharmacologial effects. Flunarizine is considered to be a calcium channel antagonist; therefore this study was aimed at investigating the effect of flunarizine (given in single doses of 5, 10 and 20mg/kg p.o.) in behavioural models in which calcium channel antagonists of the dihydropyridine type were previously studied.
Flunarizine inhibited the apomorphineinduced stereotypy and yawning behaviour in rats. It decreased the hypothermia induced by a low dose of apomorphine in mice, but not that one induced by high dose of it. The quinpirole-induced hypothermia was also reduced. In the tests used for evaluation of the effect on the serotonergic system, flunarizine decreased the 5-HTP-induced head twitches and partly antagonized the fenfluramine- and quipazine-induced hyperthermias (at a high ambient temperature). In the forced swimming test flunarizine was inactive in mice and rats.
The obtained results indicate that flunarizine exerts central antagonistic effects on the dopaminergic and serotonergic systems and has no antidepressant activity. Funarizine differs from calcium channel antagonists of the dihydropyridine type, which have no dopamine-antagonistic activity and show antidepressant-like properties.
In our previous studies we investigated central pharmacological effects of the calcium channel antagonists (CCA5) nifedipine and nimodipine coming from the chemical group of dihydropyridines (DHP), which are selective for slow calcium channels (Godfraind, 1988). Our results indicate that DHP CCAs interact with the central dopaminergic system and have an antidepressant activity (Mogilnicka et al., 1987, 1988 a; Czyrak et al., 1989). Also recent literature findings suggest the possibility of a significant interference of CCAs with dopaminergic transmission. The CCAs nifedipine and flunarizine have been shown to block the amphetamine-induced behavioural stimulation in mice (Grebb, 1986). Flunarizine caused a dose-dependent increase in the dopaminergic metabolite 3, 4-dihydroxyphenylacetic acid (DOPAC) in striatum; on the contrary, nimodipine produced a modest decrease in DOPAC levels (Fadda et al., 1989). In vitro, flunarizine, but not nimodipine, displaced 3 H]-spiperone from its binding sites. After in vivo treatment both drugs induced increase in the number of spiperone binding sites (Govoni et al., 1988).
Flunarizine (FLU) is a CCA which belongs to the chemical group of diphenylpiperazines, non-selective for slow calcium channels (Godfraind, 1988). The present paper was aimed at studying FLU with regard to its comparison with the DHP CCAs previously examined by us. In particular, we estimated the central effects of FLU on the dopamine (DA) and serotonin (5-HT) systems, as well as its antidepressant activity, the latter having been studied in two tests: the forced swimming test and the apomorphine-induced hypothermia. It is noteworthy that literature data indicate the possibility of action of FLU on the DA and serotonin systems.
Our results show that FLU is active in the tests used for evaluation of the effect on the central DA system, but its action is different from the effects induced by CCAs of the DHP type. Above all, it inhibits the APO-induced stereotypy, the behaviour considered to be caused by activation of postsynaptic DA receptors. This effect of FLU differentiates it from DHP CCAs, which do not block the APO-induced stereotypy (Shah et al., 1983; Mogiinicka et al., 1988 a). In the case of FLU, its direct blocking action on DA postsynaptic receptors may be assumed, since in vitro the drug displaces [3H]-spiperone (IC50 0.3 jiM) from the striatal synpatic membrane binding sites (Govoni et al., 1988).
Furthermore, we have found that FLU reduces dose-dependently the yawning induced by a low dose of APO. Most authors attribute yawning induced by low doses of DA agonists to stimulation of DA autoreceptors (Di Chiara et al., 1978). CCAs such as nimodipine and nifedipine induce yawning by themselves and enhance the yawning induced by DA agonists; such an increase in yawning may be blocked by BAY K 8644 a DHP calcium channel agonist (Mogiinicka et al., 1988 a). This finding indicates that the increase in yawning induced by DHP CCAs might result from the blockade of DHP binding sites. The fact that the effect of FLU on the APO.induced yawning is opposite to that of DHP CC-As suggests that the FLU-induced decrease in yawning does not depend on the interference with calcium channels, but is probably caused by its DA-antagonistic activity described above.
Moreover, in the APO-induced hypothermia test FLU also acts as do DA antagonists i.e. it reduces the hypothermia induced by a low dose (1 mg/kg) of APO in mice, but has no effect on the hypothermic action of its high dose (16mg/kg).
Neuroleptics inhibit the APO-induced hypothermia on the basis of competition for the DA receptor; hence they have a considerably more potent action towards APO given in a low dose. Hypothermia induced by high dose of APO is not antagonized by neuroleptics, but strongly antagonized by antidepressants (Puech et al., 1981). According to Puech et al. (1981) hypothermia induced by two doses of APO (1 and 16mg/kg) is proposed as a differentiation test between neuroleptics and antidepressants. The quinpirole-induced hypothermia mediated by DA D-2 postsynaptic stimulation (Faunt and Crocker, 1987) is also reduced by FLU. This finding also points to a DA-antagonistic acitivity of FLU.
Our results that concern the effect on the DA system are in accordance with other authors observations. The postsynaptic, DA-antagonistic action of FLU is indicated by an increase in the striatum DOPAC level (Fadda et al., 1989), antagonism towards the DA-evoked inhibition of prolactin secretion (Bonurelli et al., 1988; Di Renzo et al., 1988), in vitro displacement of [3H]-spiperone from its binding sites (Govoni et a!., 1988). Besides, extrapyramidal side effects, observed after FLU in the clinic (Chouza eta!., 1986), may point to the DAantagonistic action. Our suggestion that FLU exerts a DA-antagonistic action also on the presynaptic site is supported by an observation that FLU prevents the APO-induced decrease in the striatal DOPAC level, a response mediated by autoreceptors (Fadda et al., 1989).
The literature data indicate that FLU interacts also with the 5-HT receptors in the brain and in the peripheral organs, but its antiserotonergic activity is rather weak (Holmes et a!., 1984; Auguet et al., 1986; Olesen, 1989). In our present study this drug reduced the number of the 5-HTP-induced head twitches in mice and inhibited quipazine-induced hyperthermia in rats. Also the fenfluramine-induced hyperthermia was partly antagonized by FLU. All these tests are used for studying the central 5-HT2 activity; and 5-HT2 antagonists inhibit the effects of 5-HTP, quipazine and fenfluramine. Our results indicate that FLU exerts some inhibitory effects on this system; however on the basis of these results and the literature data it is impossible to say more about the mechanism of this inhibition. Our last (not published) results have shown that this effect of FLU is not shared by CCAs from the DHP group which do not influence effects induced by 5-HTP and fenfluramine.
As we found previously DHP CCAs act like antidepressant drugs, i.e. they shorten the immobility time in the forced swimming test in mice and rats (Mogilnicka et al., 1987; Czyrak et al., 1989, 1990). It seems that this action of CCAs depends on the blockade of calcium influx, since BAY K 8644, a DHP calcium channel agonist, has an opposite effect in the forced swimming test and its action can be blocked by the antagonist nifedipine (Mogilnicka eta!., 1988 b). The present studies indicate that FLU acts in this test differently from the DHP CCAs, since it does not affect the immobility time in either mice or rats. Unlike nimodipine and nifedipine which block DHP binding sites, FLU binds a phenylaikylamine binding sites of calcium channels (Murphy et al., 1984). It is possible that the blockade of this site of the channel is not important to the animals performance in the swimming test. On the other hand, the calcium antagonistic activity of FLU in this test can be masked by its DA antagonistlike action. Neuroleptics are either inactive or increase the immobility time in the forced swimming test (Porsolt et al., 1977, 1978; Borsini and Meli, 1988). As has been mentioned above, FLU has no effect on the hypothermia induced by high doses of APO, whereas tricyclic antidepressants inhibit this hypothermia (Puech etal., 1981). Thus FLU differs from DHP CCAs, which reduce the hypothermia induced by a high dose of APO (Czyrak et al., 1989), but are ineffective towards its low dose (data not published), so they are acting like antidepressant drugs.
In conclusion, the above observations suggest that FLU differs considerably in its psychopharmacological profile from CCAs of the DHP type. It may be assumed that FLU exerts a neuroleptic-like action on DA transmission. No such effect is exerted by DHP CCAs. Unlike DHP CCAs, FLU is inactive in the tests used here for evaluation on the antidepressant activity. FLU exerts some inhibitory effects on the central serotonergic (5-HT2) system.