- Abstract : Dopaminergic agonists,
apomorphine (APO) (0.025-0.25 mg/kg, s.c.),
TL-99 (0.5-3 mg/kg, s.c.) and 3-PPP (0.15-10
mg/kg, s.c.) elicited yawning in rats and the
dose-response curves of all 3 compounds showed a
bell-shaped form. Haloperidol (0.02 mg/kg, s.c.)
reduced the yawning induced by DA-agonists to
about 50%. The potencies of the DA-agonists in
inducing yawning were APO greater than TL-99
greater than 3-PPP (comparable to potencies
obtained in other in vivo tests, determining
DA-ergic activity). The findings support the
validity of the yawning phenomenon as a
screening test for DA-agonists. Additionally, it
was found that apomorphine induced yawning was
significantly and dose-dependently enhanced by
the beta-agonist, formoterol. This effect was
counteracted by scopolamine, not changed by
metergoline and further increased by
l-propranolol. These data support the hypothesis
of cholinergic involvement in yawning and
indicate a role, though unclear at present, of
beta-receptors in this behaviour.
-
- Recently, it was shown that after
administration of relatively small doses of
different dopaminergic (DA) agonists,
characteristic yawning behaviour (YN) appeared
in rats. It was suggested that this symptom
could be useful in the screening of drugs
(Mogilnicka and Klimek, 1977). The mechanism of
yawning behaviour is still unclear, however the
investigations of Urba-Holmgren, Gonzales and
Holmgren (1977) and Yamada and Furukawa (1980)
have pointed to the involvement of the
cholinergic system in this behaviour. The
cholinergic drugs, physostigmine and
pilocarpine, induce yawning behaviour which is
abolished by scopolamine. Scopolamine also
completely inhibited yawning induced by small
doses of apomorphine indicating that
apomorphine-induced yawning can result from
secondary activation of cholinergic neurones.
Assuming that small doses of apomorphine produce
an inhibition of DA-release from presynaptic
sites, resulting in activation of cholinergic
neurones (Carlsson, 1975; Chiara, Porceddu,
Vargiu, Argiolas and Gessa, 1976), Yamada and
Furukawa (1980) suggest that apomorphine elicits
yawning by stimulating presynaptic DA-receptors
and that DA-ergic inhibition and cholinergic
activation are concomitantly involved in yawning
behaviour. Larger doses of apomorphine,
stimulating postsynaptic DA-receptors, induce
hyperactivity and stereotyped behaviour which
mask yawning, so it could be expected that
DA-receptor agonists, deprived of this activity,
should produce yawning over a wide range of
doses. The effects of apomorphine were compared
with those of two recently-described
DA-agonists, TL-99 (6,7-dihydroxy-2-piperidine)
and 3-PPP (N-n
-propyl-3-(3-hydroxyphenyl)-piperidine) which
have been reported to possess selective
agonistic action at presynaptic DA-receptors
(Hjorth, Carisson, Wilkstrôm, Lindberg,
Sanches, Hacksell, Arvidsson, Svensson and
Nilson, 1981; Goodale, Rusterholz, Long, Flynn,
Walsh, Cannon and Lee, 1980). It must be added
however, that in spite of the fact that TL-99
and 3-PPP do not induce typical stereotyped
behaviour, their postsynaptic DAagonistic
properties have been demonstrated in other
pharmacological models (Martin, Haubrich and
Williams, 1980). Very recently, using a binding
assay, Williams and Totaro (1983) showed
preferential interaction between 3-PPP and
TL-99, and postsynaptic, rather than presynaptic
[3H]-APO-binding sites in striatal
membrane of rats.
-
- There have been reports indicating that
beta-adrenergic receptors contribute to the
regulation of DA-transmission (Reisine,
Chesselet, Lubezki, Chéramy and
Glowinski, 1982), as some clinical studies have
indicated that propranolol and other
J3-adrenergic receptor blockers may be of use in
the treatment of schizophrenia (Elizur, Segal,
Veret, Davidson and Atsmon, 1979; Lindstrom and
Persson, 1980). Therefore, in the second part of
these experiments, the possibility that
beta-agonists could have an influence on the
apomorphine induced yawning was
investigated.
-
- DISCUSSION
-
- As described earlier apomorphine, a
DA-agonist in a small dose, induced yawning in
rats and this behaviour was reduced by
DA-receptor blockade with neuroleptics (Dubuc,
Protalis, Colboc and Constentine, 1982;
Mogilnicka and Klimek, 1977). Recently it was
found that haloperidol reduced yawning induced
by apomorphine in doses much smaller than those
needed for inhibition of stereotypy or
hyperactivity (Dubuc et al., 1982; Nickolson and
Berendsen, 1980) which led to the suggestion
that yawning induced by apomorphine is mediated
by DA-autoreceptors. This conclusion is also
supported by present results, which show that
the compounds TL-99 and 3-PPP, thought to be
putative DAautoreceptor agonists, induced
yawning and that this behaviour was reduced by
relatively small dose of haloperidol. These
agents, in contrast to apomorphine did not
induce hyperactivity or stereotypy at any dose
level, which indicates that TL-99 and 3-PPP do
not stimulate postsynaptic DA receptors,
responsible for this behaviour. Consequently,
yawning cannot be mediated by the same
receptors.
-
- In the respect of potency for inducing
yawning (dose-ranges) apomorphine was stronger
than TL-99 and 3-PPP. It should be noted also
that the relationship is similar to that
observed in other in vivo models, such as
inhibition of motility, circling behaviour (in
6-OH-DA-lesioned rats) as well as emetic effects
in dogs (Arnt, Christensen, Hyttel, Larsen and
Svendson, 1973; Martin et al., 1981). This
suggests that the DA-receptors which mediate
yawning are similar to those leading to the
behavioural responses mentioned above.
-
- It seems likely, that if in a screening
observation a given substance induces yawning in
rats (which is blocked by DA-antagonists), there
is a high probability that the compound
possesses DA-receptor agonistic properties (it
must be emphasized also that subcutaneous
administration of DA-agonists is more efficient
than intraperitoneal administration in inducing
yawning). It is known that yawning in rats can
be induced by muscarinic stimulants
(Urba-Holmgren et al., 1977; Yamada and
Furukawa, 1980). However, if DA-antagonists
block drug-induced yawning, direct muscarinic
stimulation can be almost excluded, since
neuroleptics (except those having an
anticholinergic component) do not abolish the
yawning induced by physostigmine (Dubuc et al.,
1982).
-
- As has been mentioned, the existing data
indicate a significant, activating role of the
muscarinic system in yawning. Yamada and
Furukawa (1980) suggest that apomorphine elicits
yawning via indirect activation of cholinergic
neurones. Recently, the effects of different
DA-agonists, including TL-99 and 3-PPP on
striatal levels of acetyicholine (ACh) were
investigated over a wide dose-range (Waldmeier,
1983). By comparing the dose-ranges of
DA-agonists, influencing levels of ACh with
those inducing yawning, it was observed that
yawning appeared in ranges which paralleled
increased (not decreased) ACh levels. Thus, it
can be speculated that yawning can be mediated
by DA-receptors (postsynaptic?) which are
responsible for an increase of striatal ACh and
not by presynaptic receptors (i.e. those
reducing DA-ergic transmission and thus leading
to an increase of ACh release and consequently a
decrease in the level of ACh).
-
- Another finding of the present study is that
beta-agonists influenced apomorphine-induced
yawning. Formoterol, a beta2-agonist as well as
prenalterol, a beta1-agonist, increased
apomorphine-induced yawning. The lack of action
of another beta2-agonist, clenbuterol, is
difficult to explain at present; however,
pretreatment with clenbuterol provoked more
stereotypy-like behaviour in rats injected with
apomorphine. The sniffing, chewing and eating of
saw dust covering the cage bottom, may mask the
increase in yawning.
-
- Recently it was described that beta-agonists
enhanced behavioural responses mediated by
5-hydroxytryptophan (5-HTP) (Cowen,
Grahame-Smith, Green and Heal, 1982) and also a
role for the 5-HT-system in the yawning
phenomenon was postulated (Marini, 1981).
However the facilitation of apomorphine-induced
yawning produced by formoterol was not
counteracted by metergoline, a
5-hydroxtryptamine (5-HT) receptor antagonist.
The fact that scopolamine blocked epidoses of
yawning in rats treated with apomorphine as well
as apomorphine plus formoterol points to a
possible muscarinic component in the
potentiation induced by fi-agonists. Indeed the
enhancement of [3HI-QNB binding in the
striatum of rats by the beta-adrenergic agonist
iso-proterenol has been observed (Ehlert, Roeske
and Yamamura, 1981). Formoterol-induced
potentiation of yawning induced by apomorphine
was not abolished by the fbeta-blocker,
l-propranolol; on the contrary, yawning was
further enhanced. l-Propranolol, by itself
potentiated yawning induced by apomorphine and
this effect seemed to be additive to the action
of formoterol. The fact that both beta-receptor
stimulation and blockade produced the same
facilitating effect on apomorphine-induced
yawning is confusing. It is not possible at
present either to explain this phenomenon or to
derive any conclusions about the role of
beta-receptors in yawning. Nevertheless,
yawning, although the mechanism is still
unknown, seems to be a reliable behavioural sign
of the DA-agonistic action of drugs.
-
- -Mogilnicka E,
Wedzony K, Klimek V, Czyrak A Desipramine
induces yawning behaviour in rats
Neuropharmacology 1986; 25; 7; 783-6
- -Mogilnicka E,
Klimek V Drugs affecting dopamine neurons
ans yawning behavior. Pharmacol Biochem Behav
1977; 7; 303-305
- -Molgilnicka
E REM sleep deprivation changes behavioral
response to catecholaminergic and serotoninergic
receptor activation in rats Pharmacol Biochem
Behav 1981; 15; 1; 149-151
- -Mogilnicka
E, Boissard CG, Delini-Stula A Effects of
apomorphine, TL-99 and 3-PPP on yawning in rats.
Neuropharmacology. 1984; 23; 1; 19-22
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