Pharmacological
characteristics of dopamine agonists on yawning
behavior in rats
Protais P, Dubuc I, Constentin J
laboratoire de
pharmacodynamie et pysiologie, faculté
médecine Rouen, France
Introduction : Several reports have
indicated that the reference DA agonist APO
modulates yawning in rats in a biphasic manner;
there is a dose-dependent induction of yawns for
low doses of APO and a dose-dependent decrease
of the yawning frequency for higher doses. Such
a biphasic effect has been interpreted as the
successive involvement of DA autoreceptors and
postsynaptic DA receptors. According to this the
lower doses of APO would stimulate DA
autoreceptors and therefore decrease tonic
doparninergic transmission with a consequent
induction of yawning. On the contrary, the
higher doses of APO, by stimulating postsynaptic
DA receptors, would restore a high apparent
level of the dopaminergic transmission
associated with a disappearance of yawns. In
fact, if other hypotheses could explain this
biphasic effect, most would rest on the
involvement of two subtypes of DA receptors
differing by their relative sensitivity to APO.
It was therefore of interest to check whether
other known DA agonists belonging
-to various chemical classes displayed an
activity similar to that of APO,
-to investigate the relative sensitivity to
various neuroleptics of the DA receptors
involved in the DA agonist-induced appearance
and disappearance of yawns
-to consider the possible relationship
between the Da agonist-induced disappearance of
yawns and appreance of stereotypies.
Results concerning these three experimental
steps are presented in this paper.
Discussion : We confirm the previous
report (Holmgren
and Urba-Holmgren, 1980;Yamada),
that the reference DA agonist APO biphasically
influences yawning in rats: yawns appear (YAWN
APP.) at low doses and disappear (YAWN DIS.) at
higher doses. DA receptors are clearly involved
in these opposed effects of APO on yawning since
YAWN APP. and YAWN DIS. were produced by all the
purported DA agonists tested and were affected
by most of the neuroleptics tested. This
biphasic effect was also observed when the time
course of yawning induced by 0. 15 mg - kg APO
was considered. This time-dependent dual effect
and the biphasic dose-response curve seem
connected with the brain concentration of APO.
Whereas the yawning frequency was highest at the
beginning and end of the observalion period i.e.
when the brain concentration of APO was low, the
yawning frequency was low in the middle of the
observation period i.e. when the brain
concentration of APO was highest. The variations
in the brain concentration of DA agonists might
account, al least in part, for the higher
frequency of yawns observed with bromocriptine.
This drug has a relatively long half-life and
crosses the blood brain barrier with difficulty
so that an optimal and stable brain
concentration could be obtained for the
induction of yawns during the whole period of
observation.
All the neuroleptics tested antagonized
APO-induced YAWN APP. Furthermore, increasing
doses of most of the neuroleptics (i.e.
haloperidol, chlorpromazine, mezilamine,
thioridazine and metoclopramide) made yawning
behaviour reappear (YAWN REAPP.) in animals
treated with 0.6 mg -kg, APO. YAWN REAPP. likely
resulted from the blockade of the DA receptors
involved in YAWN DIS. with a persistent
stimulation of the DA receptors mediating YAWN
APP. For these neuroleptics, the apparent ID50
for the antagonisrn of APO-induced YAWN DIS.
were similar to those obtained for the
antagonism of YAWN APP. In addition, at 0.6 mg
-kg, the APO brain concentration was
approximately 6 fold that at which there was
apparent maximal stimulation of the DA receptors
involved in YAWN APP. (0.1 mg.kg-1 APO).
Therefore, it seems that the
agonist/antagonist concentration ratio favours
the prevalent action of APO on the DA receptors
involved in YAWN APP. This is supported by the
fact that yawns decreased then were suppressed
when the doses of haloperidol were further
increased. So il appears that, in 0.6 mg - kg
APO-injected rats, the response to increasing
doses of haloperidol followed the bell-shaped
doseresponse curve of APO in the opposite
direction.
In contrast, increasing doses of clozapine
and of some benzamide neuroleptics (sulpiride,
veralipride and DAN 2163) were unable to produce
YAWN REAPP. in 0.6 mg -kg APO-injected rats. The
lack of YAWN REAPP. with clozapine was probably
due to its antimuscarinic properties since
antimuscarinic agents oppose APO-induced yawns.
The antimuscarinic activity of clozapine is
shown by the antagonism of physostigmine-induced
yawns by a low dose of this drug (about twice
its ID50 on 0.1 mg - kg APO-induced yawns). It
is then possible to consider that stimulation of
the DA receptors involved in YAWN APP. occurs in
rats treated with clozapine and 0.6 mg - kg APO
but that the effect of their stimulation is
simultaneously suppressed at cholinergic
synapses.
Similar results would be obtained with other
drugs displaying more antimuscarinic than
antidopaminergic activity. This does not seem to
be the case for thioridazine which induced YAWN
REAPP. in 0.6 mg - kg - 1 APO-injected rats and
hardly antagonized physostigmine-induced yawns.
The lack of YAWN REAPP. with sulpiride,
veralipride and DAN 2163 does not seem to have
the same meaning. Antimuscarinic activity is
ruled out since antagonism of
physostigmine-induced yawns was obtained neither
with sulpiride nor, under similar conditions,
with veralipride and DAN 2163 (unpublished
data). Also, it has not yet been reported that
benzamides might share other pharmacological
properties able to influence yawning in the same
way as antimuscarinic drugs. That systemically
injected benzamides modified, relatively to
other neuroleptics, the access or the regional
distribution of APO in the brain could explain
their peculiar effects on yawning. However, this
interpretation is unlikely to be correct since
similar results were also found following inj
iv. administration (unpublished data).
Therefore, whereas the neuroleptics which
induced YAWN REAPP. in 0.6 mg - kg APO-injected
rats had similar ID50 on both APO-induced YAWN
APP., YAWN DIS. and sniffing, sulpiride,
veralipride and DAN 2163 antagonized APO-induced
YAWN APP. at doses niarkedly lo\ver than those
at which they opposed APO-induced sniffing. The
ratio of their ID50 (sniffing/yawning) was
between 3 (sulpiride) and 22 (veralipride).
Thus, the lack of YAWN REAPP. established with
sulpiride, veralipride and DAN 2163 in 0.6 mg
-kg APO-injected rats suggests that, as DA
agonists, these benzamides would recognize ln a
differentiated manner the DA receptors involved
in YAWN APP. and YAWN DIS. respectively.
In this view, the DA receptors mediating
YAWN APP. would display a high relative
sensitivity for DA agonists and would be blocked
by low doses of all neuroleptics, either the
'classical' or the 'atypical' ones, including
the three above benzamides. In contrast, the DA
receptors mediating YAWN DIS. would display a
low relative sensitivity for DA agonists and
would be blocked by low doses of neuroleptics,
except sulpiride, veralipride and DAN 2163. The
pharmacological characteristics of the latter DA
receptors appear similar to those of the
receptors mediating APO-induced sniffing. These
data may be compared with the ability of
sulpiride and DAN 2163 to distinguish between
the D-2 and D-4 subtypes of DA binding sites
(Sokoloff et al., 1980; Schwartz et al., 1983).
The property of sulpiride, veralipride and DAN
2163 to discriminate between two DA receptor
subtypes is not common to all the benzamide
neuroleptics since it is not shared by
metoclopramide.
In the same range of doses as for yawning, DA
agonists modulate in a biphasic manner other
effects such as climbing locomotor activity ,
penile erections or EEG activity. These biphasic
effects have generally been interpreted as the
consequence of the action of DA agonists at the
same synapses: whereas low doses of DA agonists
would stimulate autoreceptors, higher doses
would stimulate postsynaptic receptors. Such an
interpretation was also suggested for yawning.
The easy antagonism of 0.1 mg - kg - 1
APO-induced YAWN APP. by sulpiride could be
consistent with this hypothesis since DA
autoreceptors seem to have a relatively high
affinity for this drug.
However, as an alternative it may be
suggested that yawning and sniffing would be
mutually exclusive. This hypothesis is
supported
- by the similar FD50 of DA agonists on YAWN
DIS. and the induction of sniffing,
- the similar ID,, of Inost DA antagonists
to oppose YAWN DIS. and sniffing,
- the opposite development of the time
courses of 0. 15 mg - kg APO-induced yawning and
sniffing
- the hypersensitivity to APO of sniffing
observed concomitantly with hypersensitivity to
APO-induced YAWN DIS. in rats with
6-hydroxydoparnine-lesioned olfactory tubercles.
Moreover, the decreased yawning frequency
observed in this latter condition does not seem
connected with the disappearance of DA
autoreceptors resulting from the dopaminergic
denervation of olfactory tubercles since DA
neurons projecting to the septum are thought to
be involved in yawning.
Therefore, the lack of YAWN REAPP. in rats
injected with 0.6 mg - kg APO that we observed
with ( ± )- or ( - )-sulpiride, veralipride
and DAN 2163 (at doses for which these
benzamides antagonized sniffing) could depend on
the ability of these drugs to distinguish
between the DA receptors involved in YAWN APP.
and in sniffing.
In conclusion, the antagonism byneuroleptics
of 0.1 mg -kg APO-induced yawning and the
effects of increasing doses of these drugs on
both sniffing and yawning in 0.6 mg - kg
APO-injected rats may be indicative of the
property of DA antagonists to distinguish
between two DA receptor subtypes. Ilowever,
anticholinergic activity of these agents must
then be simultaneously excluded.
-Protais
P, Dubuc I, Constentin J Pharmacological
characteristics of dopamine agonists on yawning
behavior in rats. Eur J pharmacological 1983;
94; 271-280
-Protais P,
Dubuc I, Colboc O, Costentin J Étude
des récepteurs dopaminergiques dont la
stimulation induit ou inhibe les
bâillements chez le rat. J Pharmacologie
1982; sup1; 191
-Protais
P, Windsor M, Mocoer E, Comoye E
Post-synaptic 5-HT1A receptor involvmement in
yawning and penile erections induced by
apomorphine, physostigmine and MCPP, in rats
Psychopharmacology 1995; 120; 4; 376-383
