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.
Introduction
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.
Discussion
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.
