Post-synaptic
5-HT1A receptor involvemement in yawning and
penile erections induced by apomorphine,
physostigmine and MCPP in rats
Protais P, Windsor M, Mocoer E, Comoye
E
Laboratoire de physiologie
UFR Médecine-Pharmacie Rouen
France
Apomorphine and mCPP induced yawning
associated with penile erections in rats,
whereas physostigmine induced only yawns.
Apomorphine-induced yawning and penile erections
were antagonized by low doses of raclopride,
whereas physostigmine-induced yawning and
mCPP-induced effects were only partly inhibited
at high doses of raclopride. Scopolamine as well
as clozapine antagonized yawning and penile
erections induced by apomorphine, mCPP and
physostigmine. Similarly, the 5-HT1A agonists
8-OH-DPAT and S 14506 inhibited yawning and
penile erections induced by apomorphine, mCPP
and physostigmine, and at similar doses induced
lower lip retraction and hyperreactivity to
handling. The beta/5-HT1A antagonist tertatolol
reversed the inhibitory effects of 8-OH-DPAT and
S 14506 on drug-induced yawning and penile
erections and increased apomorphine- and
physostigmine-induced yawn frequency but not
penile erection frequency. Like tertatolol,
propranolol increased apomorphine- and
physostigmine-induced yawn frequency, whereas
ICI 118551 increased only physostigmine-induced
yawning. 8-OH-DPAT- and S 14506-induced lower
lip retraction and hyperreactivity to handling
were also significantly antagonized by
tertatolol. Finally, p-chlorophenylalanine
pretreatment produced about 95% depletion in
5-HT in hypothalamus, hippocampus, striatum and
frontal cortex and modified neither the
responses of the inducing drugs nor the
inhibitory effects of 8-OH-DPAT and S 14506 on
drug-induced yawning and penile erections. These
data suggest (i) that a final cholinergic
mechanism blocked by scopolamine and clozapine
is involved, in drug-induced yawning and penile
erections, (ii) that the effects of S 14506
depend upon stimulation of 5-HT1A receptors,
(iii) that the inhibitory effects of 5-HT1A
agonists on yawning and pende erections probably
occurred at final steps on the pathways involved
in the expression of yawning and penile
erections and that these effects could be
related to other effects of the 5-HT1A agonists,
(iv) that a tonic inhibitory P influence could
interfere with the expression of yawning but not
with that of penile erections and (v) that
presynaptic 5-HT1A receptors do not seem to play
an important role in the inhibitory effects of
5-HT1A agonists on druginduced yawning and
penile erections in rats.
Introduction
Several neurotransmitters appear to be
involved in yawning and pende erections in rats.
Even if it is likely that the two behaviours are
independent, they were reported as both induced
by classical neurotransmitters agonists such as
dopamine (DA) agonists, as well as by
neuropeptides such as ACTH, (alpha-MSH and
oxytocin. In contrast, muscarinic receptors
agonists cholinesterase inhibitors appear to
induce only yawning. In the case of
serotoninergic agonists, it was essentially
reported that a serotoninergic link was involved
in yawning and that mCPP, a metabolite of
trazodone acting at both 5HT1B abd 5HT2C
receptors, induced yawning, mCPP and other 5HT2C
receptors agonists also appeared potent in
inducing penile erections, whereas 5HT1A and
5HT2A agonist were reported to inhibit
mCPP-induced penile erections.
In the course of studies on S 14506, a
highly potent 5-HT1A agonist, we observed
inhibition of apomorphine-induced yawning and
pende erections. In another study, it was
observed that S 14506 inhibited some dopamine
agonist-induced behaviours by blocking D2
dopamine receptors. The aim of the present study
was to determine the pharmacological specificity
of the inhibition exerted by S 14506 on
apomorphine-induced yawning and penile erections
and to extend our initial observation to yawning
and penile erections induced by physostigmine
and mCPP. For this purpose, S 14506 as
essentially compared to the prototypic 5-HTI A
agonist, 8-OH-DPAT. The selective D2 dopamine
antagonist raclopride, the muscarinic antagonist
scopolamine and the atypical neuroleptic
clozapine were used to quantify the specificity
of drugs inducing yawning and penile erections.
[...]
Discussion : The present results
confim previous work pointing to the involvement
of dopaminergic, cholinergic and serotoninergic
synapses in both yawning and penile erections in
rats. However, there are differences between the
ability of apomorphine, physostigmine and mCPP
to induce the two responses.
Yawning was induced by apomorphine,
physostigmine and mCPP. The antagonism by
scopolamine of yawning induced by the three
compounds suggests that a cholinergic link was
likely as a final step on the neuronal pathways
involved in this behaviour. The effects of
raclopride confirmed the dopaminergic origin of
apomorphine-induced yawning, and that
physostigmine and mCPP probably acted downstream
from DA receptors to induce yawning. Contrary to
raclopride, clozapine inhibited the effects of
apomorphine, physostigmine and mCPP on yawning
at roughly similar doses. Since clozapine acts
as an antagonist at various muscarinic receptor
subtypes ) in addition to its antagonist
activities at DA Dl and D2 receptors and at
5-HT2c receptors, it is likely that the effects
of clozapine resulted either from its
anticholinergic component (similarly to
scopolamine) or that, in spite of the
differences in affinity at various receptors
observed in in vitro binding studies, clozapine
acted in vivo at roughly similar doses on these
various receptors.
Yawning induced by apomorphine, physostigmine
and mCPP was inhibited by 8-OH-DPAT and S 14506.
This inhibitory effects probably resulted from
the stimulation of 5-HT1A receptors, since the
two compounds were described as 5-HT1A agonists
at doses used in the present stuldy. DA receptor
antagonist properties of S 14506 were observed
at far higher doses. Furthermore, at the doses
used in the present study, 8OH-DPAT and S 14506
elicited lower lip retraction, an effect
described as resulting from the stimulation of
5-HT1A receptors, and hyperreactivity to
handling.
Hyperreactivity to handling is not
classically studied as a component of the
behavioural 5-HT syndrome. However, this
reactivity to handling is frequently observed in
animals treated with various serotoninergic
drugs. In the present study, this phenomenon
appeared of high importance since it is well
known that rats stressed during injections
usually have a low frequency of yawning.
Therefore, it may be asked whether
hyperreactivity to handling could reflect a
state of stress and therefore non-specifically
inhibit drug-induced yawning. 8-OH-DPAT- and S
14506 induced inhibition of drug-induced
yawning, lower lip retraction and
hyperreactivity to handling were antagonized by
the beta/5-HT1A antagonist tertatolol.
In fact, tertatolol was able not only to
oppose the inhibition by 8-OH-DPAT and S 14506
of apomorphine and physostigmine induced yawning
but also to increase the effects of these two
yawning inducing drugs. Such a potentiation by
tertatolol was not found on mCPP-induced yawning
or on the components of the behavioural 5-HT
syndrome which were only partially antagonized
by 5 mg/kg tertatolol. Since potentiation by
tertatolol of apomorphine- and
physostigmine-induced yawning could be observed
simultaneously with partial antagonism by
tertatolol of hyperreactivity to handling, this
tends to suggest that hyperreactivity to
handling and inhibition of yawning were not
really related.
That tertatolol increased apomorphine- and
physostigmine-induced yawning could be due to
permanent inhibition of yawning linked either to
a serotoninergic tone and a basal stimulation of
5-HT1A receptors or to a catecholaminergic tone
and a basal stimulation of
beta-adrenoreceptors. In order to test the
influence of an inhibition of yawning through
the tonic stimulation of 5-HTIA receptors,
drug-induced yawning was studied in rats
pretreated with the serotoninergic depletor
pCPA.
The virtually complete depletion of 5-HT in
various brain areas possibly involved in
yawning, weakly increased physostigmine-induced
yawning but did not modify apomorphine-induced
yawning. Our data contrast with those of Okuyama
et al. (1987) and of Matsurnoto et al. (1989),
suggesting a potentiation of DA agonist-induced
yawning following pCPA pretreatment. These
discrepancies could be due to differences
especially in the procedure of administration of
pCPA and in the extent of the 5-HT depletion. In
our study, the changes in monoamine levels
induced by the pCPA pretreatment permitted the
conclusion that 5-HT transmission was virtually
abolished, whereas other forms of monoamine
neurotransmission were unaffected. Therefore, it
seems that, if a tonic stimulation of 5-HT1A
receptors inhibited yawning, its influence
was weak, and that the beta-adrenergic
antagonist component of tertatolol was probably
involved in the potentiation of apomorphine-and
physostigmine-induced yawning by thisbeta/5-HT1A
antagonist. This conclusion is consumed by
previous data with various adrenoreceptor
antagonists (Yarnada et al. 1989) similar to our
results with tertatolol and propranolol, by the
increased physostigmine-induced yawning in rats
treated with the selective P2 antagonist ICI
118.551 and by the decreased yawn frequency
reported in rats pretreated with the P2 agonist
salbutamol.
However, since tertatolol and propranolol
increased apomorphine- and physostigmine-induced
yawning in a more marked manner than ICI 118
551, we cannot exclude that simultaneous
blockade of fl adrenoreceptors and of 5HT
receptors could be responsible for tertatolol
and propranolol effects. Indeed, pretreatment
with pCPA could also suppress a tonic
facilitatory serotoninergic influence involved
in the expression of yawning. The interpretation
for the involvement of the fi-adrenergic
antagonist properties of tertatolol in the
potentiation of apomorphine-and
physostigmine-induced yawning is nevertheless
further suggested by the fact that low doses of
8-OH-DPAT, which could stimulate preferentially
presynaptic 5-HTIA receptors, and therefore
decrease the serotoninergic tone, were unable to
increase apomorphine and physostigmine-induced
yawning. In addition, since the 8-OH-DPAT and S
14506-induced inhibition of drug-induced yawning
was not modified in pCPA-pretreated rats, it is
like that postsynaptic 5-HT1A receptors are much
more involved in this effect than presynaptic
5-HT1A receptors. It seems possible to draw the
same conclusion 8-OH-DPAT- and S 14506-induced
lower lip retraction and hyperreactivity to
handling. However, our conclusion must be
confirmed by further experimente using silent
and selective antagonists since it was reported
that pCPA pretreatment could modify the activity
of drugs (ritanserin) on dopaminergic neurons.
Roughly similar results were obtained on
penile erections. Despite the inability of
physostigmine to induce penile erections, the
antagonism by scopolamine, and also by
clozapine, of penile erections induced by
apomorphine and mCPP suggest that a final
cholinergic link is also involved in this
behaviour. In a manner similar to that observed
on yawning, we conclude that postsynaptic 5-HT1A
receptors are likely to be involved in
8-OH-DPAT- and S 14506-induced inhibition of
drug induced penile erections. However,
drug-induced penile erections appeared more
sensitive to the effects of 5-HT1A agonists and
did not seem to be modulated by beta
adrenoreceptors, since beta antagonists were
unable to increase apomorphine- and mCPP-induced
penile erections.
In conclusion, our results (i) suggest that
both inducing drugs exerted their effects by a
final cholinergic mechanism blocked by
scopolamine and clozapine, (ii) confirm the
5-HT1A agonist properties of S 14506, (iii)
indicate that the inhibitory effects of 5-HT1A
agonists on yawning and penile erections
probably occurred at final steps on the pathways
involved in the expression of yawning and penile
erections and that these effects could be
related to other effects of the 5-HT1A agonists,
(iv) suggest that presynaptic 5-HT1A receptors
do not seem to play an important role in the
inhibitory effects of 5-HT1A agonists on
drug-induced yawning and penile erections in
rats and (v) confirm that tonic inhibitory P2
influence could interfere with the expression of
yawning but not with that of penile
erections.
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P, Dubuc I, Constentin J Pharmacological
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-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
