- The almost fortuitous discovery of
antipsychotic agents which are devoid of
cataleptogenic activity in rats has led to a
search for tests which will easily screen for
these drugs, called "atypical" neuroleptics. It
is hoped by such tests to select antipsychotic
drugs which do not cause extrapyramidal symptoms
in man. Some of these tests have been reported
previously: the antagonism in mice of
apomorphine-induced climbing behaviour (Protais
Costentin and Schwartz, 1976), the potentiation
of morphine-induced catalepsy in rats or the
conversion of the running fit elicited in mice
by morphine into a marked hypokinesia (Barghon,
Protais, Colboc and Costentin, 1981). With the
view to developing other tests, attention was
directed to the various behavioural effects of
apomorphine, in order to see which of them were
antagonized by "atypical" neuroleptics. An
antagonism by these drugs of apomorphine-induced
yawninq is reported here.
METHODS : Male Wistar rats (IFFA
CREDO), weighing 200-250 g were used. They were
housed in a well-ventilated room at an ambient
temperature of 220C and under artificial
illumination (light on between 8 a.m. and 8
p.m.) The rats were separated without food in
wire mesh cages (L = 25 cm, W = 18 cm, H = 30
cm) as soon as the neuroleptics agents were
injected For testing, the animals were injected
subcutaneously with either apomorphine or
physostigmine, and the yawns they displayed
during the following 60 min were counted. The
mean number of yawns of each group was compared
with that of the respective control group by use
of Student's t test.
-
- RESULTS AND DISCUSSION :As described
by Holmgren and Urba-Holmgren (1980), increasing
doses of apomorphine modified the number of
yawns occurring in rats in a biphasic manner:
durinq the 60 min. following a subcutaneoys
injection of apomorphine the number of yawns
increased from 12.5 µg.kg to 100
µg.kg-1 of apomorphine then decreased (the
yawns disappearing at a dose of approximately
600 µg.kg-1. Using 100 µg.kg-1 of
apomorphine, some neuroleptic drugs, especially
"atypical" ones, were tested, determining
whenever possible their ID50. Whereas
domperidone, a dopamine antagonist known not to
pass the bloodbrain barrier, was ineffective in
doses up to 0.5 mg.kg-1 the classical
neuroleptic haloperidol and the four best known
"atypical" neuroleptics were effective
antagonists in relatively small doses.
Considering the biphasic aspect of the
dose-response curve for apomorphine, in order to
determine whether the neuroleptic-induced
disappearance of yawns in animals treated with
100µg.kg-1 of apomorphine resulted from a
true antagonism or, conversely, from a
potentiation of its action, the effect of the
ID50 of these neuroleptics, opposed to a smaller
test dose of apomorphine (50 pg.kg-~ ) wai
determined. Whereas in the animals treated only
with apomorphirie (50 µg.kg , s.c.) the
number of yawns was similar to the preceding
one, ie. 11.7 ± 2.0 (mean ± S.E.M. of
12 animals), it was 2.9 ± 0.9 in
haloperidol-pretreated rats (mean ± S.E.M.
of 8 animals, P < 0.01), 3.2 ± 1.4 in
sulpiride-pretreated rats (mean ± S.E.M. of
9 animals, P < 0.01, 5.3 1.5 in
thioridazine-pretreated rats (mean ± S.E.M.
of 8 animals, P < 0.05), 3.0 ± 2.0 in
clozapine-pretreated rats (mean ± S.E.M. of
8 animals, P < 0.02) and 4.0 ± 1.0 in
mezilamine-pretreated rats (mean ± S.E.M.
of 8 animals, P < 0.02). In addition,
pretreatment of the rats with increasing doses
of sulpiride only caused a d?se-dependent
inhibition of the yawning behaviour elicited by
either 25 µg.kg- or 100 µg.kg-1 of
apomorphine. Therefore it may be concluded that
an antagonism was observed, and not a
potentiation.
The antagonism by classical neuroleptics is
well documented, particularly for fluphenazine
(Yamada and Furukawa, 1980), spiperone (Holmgren
and Urba-Hol:mgren, 1980), butaclamol and
pimozide (Mogilnicka and Klimek, 1977) but has
not been considered here (except for
haloperidol).
A dopaminergic-cholinergic link has been
shown to be involved in yawning behaviour
(Yamada and Furukawa, 1980; Holmgren and
Urba-Holmgren, 1980) such that central
muscarinic receptor blocking agents oppose the
yawning caused by dopamine agonists. The absence
of cataleptogenic activity by clozapine has been
claimed to depend on its anticholinergic
properties, correcting the extrapyramidal
symptoms resulting from the blockade of dopamine
receptors. Such a dual action, ie.
antidopaminergic and anticholinergic, would not
limit the yawning test since it would lead to an
increase in the antagonism of
apomorphine-induced yawning.
In similar conditions to those used
previously, but this time using the
cholinomimetic drug physostigmine (75 µg.kg
, s.c.) to induce yawns, the possibility that
anticholinergic properties of the "atypical"
neuroleptics were involved in the antagonism of
apomorphine-induced yawning, was tested. For
this the neuroleptics were tested at doses
corresponding to approximately twice the
ID50s.
The physostigmine-induced was not decreased
to a significant extent (P 0.05) ln rats
pretreated with haloperidol, mezilamine,
sulpiride or thioridazine. However, the latter
drugs, which is known to possess anticholinergic
activity, was an effective antagonist when
tested in a dose corresponding to 5 times it
ID50 in the apomorphine-induced yawning
behaviour test. Finally, clozapine, in a dose
corresponding to its ID50 for
apomorphine-induced yawning behaviour, induced a
clear antagonism which was complete for twice
this dose (Fig. 2). Therefore it appears that
only with clozapine was an strong
anticholinergic component involved in the
suppression of apomorphine-induced yawning.
However, this does not contradict the well-known
anticholinergic properties of thioridazine
(Miller and Hiley, 1974), but only indicates
that for doses at which the dopamine receptors
involved in yawning were blocked, the
cholinergic receptors relaying the apomorphine
effect were virtually not blocked. This is in
agreement with the relative anticholinergic and
antidopaminergic activity reported from binding
studies by Laduron and Leysen (1978) .
This dopamine-acetylcholine interaction shows
that the inhibition of apomorphine-induced
yawning would not provide a specific methods for
screening neuroleptics, since it could lead to
the selection of agents having only the central
anticholinergic activity and possibly other
drugs interacting with other neurotransmitters.
However, the present approach, combining the
antagonism of yawning elicited by apomorphine
and by physostigmine, could be of interest to
extend investigations of neuroleptics, and
particularly ..atypical" ones, after their
selection by the use of other tests, such as the
climbing test (Protais et al., 1976; Marcais,
Protais, Costentin and Schwartz, 1978). In fact,
antimus«E-arinic agents potentiate
apomorphine-induced climbing behaviour
(unpublished data), whereas they antagonize
apomorphine-induced yawning; therefore these
approaches seem complementary.
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