Yawning-penile
erection syndrome as a model for putative
dopamine autoreceptor activity
Gower AJ, Berendsen H et al.
Department of CNS
pharmacology, Organon, The
Nederlands
Introduction
Yawning can be elicited in experimental
animals by the dopamine agonists, apomorphine,
norpropolnorapomorphine and lisuride.
Furthermore apomorphine-induced yawning can be
antagonised by doamine antagonists: haloperidol,
fluphenazine, spiperone, butaclamol, pimozide
and sulpiride. Thus, drug-induced yawning
apparently involves doamine receptors.
Apomorphine has biphasic effects on
behaviour, decreasing motor activity at low
doses and causing stimulant effects such as
hyperactivity and stereotypy at high doses. The
stimulant effects have been attributed to a
postsynaptic agonist action whereas the motor
inhibition is believed to be mediated by
activation of central dopamine autoreceptors.
This latter hypothesis is derived from the close
correlation between the doses which inhibit
motor activity and the doses which reduce
dopaminergic activity, including synthesis, in
the brain.
Since yawning is elicited by low doses of
the dopamine agonists it has been proposed that
this response may be mediated via a dopamine
autoreceptor. If such a suggestion is correct
and the elicitation of yawning is a
characteristic common to dopamine autoreceptor
agonist, it would provide a behavioural model
for evaluating potential new autoreceptor
agonists. Such a model would be useful in view
of current thinking that dopamine autoreceptor
agonists may represent a novel class of
antipsychotic agents. Apomorphine and n-propyl
norapomorphine have been reported to alleviate
schizophrenic symptoms in man.
In order to investigate drug-induced yawning
as a possible model for dopamine autoreceptor
agonist activity, we determined the ability of
several drugs to elicit yawning. We evaluated
the effect of both the established dopamine
agonists, apomorphine and n-propyl
norapomorphine and of some new dopamine
agonists. These new drugs included TL-99, 3-PPP
racemate and pergolide which share certain
dopaminergic actions such as their ability to
inhibit the accumulation of DOPA in
gamma-butyrolactone-treated rats but which
differ in other respects. For example, pergolide
causes stereotyped hyperactivity whereas TL-99
and 3-PPP do not. We also tested SK&F 38393.
This is a dopamine agonist with a novel profile
of action in that it does not affect dopamine
turnover in the brain or cause emesis or
stereotypy but does stimulate dopamine-sensitive
adenylate cyclase in vitro and cause
contralateral rotation in rats prepared with
unilateral 6-hydroxydopamine lesions of the
nigrostriatal pathway. In addition we tested
clonidine which, like the dopamine agonists,
reduces locomotor activity but has no properties
which can be ascribed to a dopamine mimetic
action. At the same time we investigated the
ability of all these drugs to produce penile
erections since such an effect has been
described in association with drug induced
yawning. We report here that physostigmine, a
drug without dopamine agonist activity but which
induces yawning, can be differentiated from
dopamine agonists by its lack of ability to
cause penile erection. Finally we evaluated the
effects of some antagonists against drug-induced
yawning and penile erection.
Discussion
In addition to apomorphine and NPA, that are
already known to induce yawning, pergolide,
3-PPP, TL-99 and N,N-dipropyl A-5 ,6-DTN all
caused pronounced yawning. The yawning occurred
at low doses and was always accompanied by an
increase in penile erections. In accordance with
previous findings the responses elicited by
morphine were prevented by pretreatment with
haloperidol and sulpiride. Pergolide,
N,N-dipropyl A -5,6-DTN and 3-PPP were also
antagonised by haloperidol. It has already been
shown that haloperidol and sulpiride antagonise
NPA-induced yawning and NPA-induced penile
erection. Due to lack of TL-99, the antagonism
of the effects of his drug could not be tested.
These data plus dditional evidence cited in the
introduction indicate that both responses are
mediated via a dopamine receptor.
There is a close resemblance between the
potencies of these drugs in causing yawning and
their potencies in biochemical tests considered
to identify dopamine autoreceptor activity. The
order of potency for the dopamine agonists in
causing the YE syndrome at peak effect was NPA-
N,Ndipropyl A-5,6-DTN, pergolide, apomorphine
TL-99, 3-PPP. The same order of potency was
obtained by Martin et al. (1982) for the ability
of these drugs to inhibit the accumulation of
striatal DOPA caused by gamma-butyrolactone and
NSD 1015 treatment. There is a striking
similarity between the optimal doses for causing
yawning and the ED50s cited by Martin. Using a
different index which may also indicate
autoreceptor activity. Feenstra et al. (1980)
reported that N,N-dipropyl A-5,6-DTN caused a
70% depletion of striatal homovanillic acid at a
concentration of 0.06 µmol/kg i.p.,
equivalent to 15.6 µg/kg. This is close to
the optimal dose (20 µg/kg) of this drug
for eliciting yawning. Furthermore the potencies
of the dopamine agonists in this study are
dissociated from their potencies for eliciting
other dopamine mediated behaviours such as
emesis, stereotypy and rotation.
SK&F 38393 did not cause yawning and or
slightly enhanced penile erections. This drug do
not reduce dopamine turnover or inhibit dopamine
release in brain slices; SK&F 38393 is thus
parently devoid of autoreceptor activating
action.
All these findings show that the receptor
involved in the induction of yawning and penile
erections has characteristics in common with the
dopamine autoreceptor. One would expect that
postsynaptic dopamine receptor blockers should
induce the YE syndrome by reducing functional
activity on the dopamine receptor. Although some
potentiation by fluphenazine and haloperidol of
physostigmine-induced yawning has been observed,
there is no report of a true YE syndrome being
elicited by a neuroleptic by itself. This could
be related to additional effects of these drugs
on other receptors such as noradrenergic,
serotonergic or cholinergic or to a lack of
specificity for subpopulations of dopamine
receptors. Our results do not imply that the YE
syndrome is mediated by autoreceptors per se
since we have no evidence concerning the
location, but rather that the receptors involved
have similar characteristics.
3-PPP is a racemic mixture of two isomers,
each having a different profile of activity. At
low doses (+ )-3-PPP inhibits DOPA formation in
y-butyrolactone-treated rats and reduces
locomotor activity, indicating a presynaptic
autoreceptor action. At higher doses (+ )-3-PPP
has effects which point to postsynaptic receptor
agonist activity: it increases levels of
striatal acetylcholine (ACh) and causes
hyperactivity. The YE syndrome observed with
this isomer is therefore consistent with the
possibility that (+ )-3-PPP is a selective
dopamine autoreceptor agonist at low doses. The
(-)-isomer appears to be both weaker and less
selective in its actions at dopamine receptors.
There is, as with (+ )-3-PPP, evidence
indicative of an autoreceptor agonist action.
However, unlike (+ )3-PPP, this isomer also
behaves as a postsynaptic blocker in that it
antagonises dopamine stimulation of
dopamine-linked adenylate cyclase and also
decreases striatal ACh levels. The inability of
(- )-3-PPP to cause significant yawning and
penile erections is consistent with its reported
profile of activity.
The negative results obtained with clonidine
indicate that stimulation of
alpha2-adrenoceptors does not cause yawning or
penile erections. The lack of effect also shows
that yawning is not concomitant with reduced
activity. This demonstrates that, in terms of
selectivity, there is a great advantage in using
the YE syndrome instead of hypomotility as a
behavioural index of autoreceptor agonist
activity. These findings are particularly
pertinent in the case of reports that TL-99 and
N,N-dipropyl A-5,6 DTN possess substantial
a2-agonist activity especially since Horn et al.
showed that the hypomotility caused by TL-99
was, in fact, mediated in part by
activation.
Physostigmine also caused yawning,
confirming previous findings. It is distinct
from dopamine agonists because it had no effect
on penile erections. The antagonism of
apomorphine yawning by atropine supports
previous findings and suggests that a
cholinergic-dopaminergic linked system in the
striatum is involved in yawning induction.
The observation that A-5,6 DTN did not
produce yawning or penile erections is relevant
to the search for the site at which drugs act to
cause the YE syndrome. A-5,6 DTN causes
stereotypy, hyperactivity and rotation when
given intracerebrally showing that it has potent
dopaminergic activity but it fails to penetrate
into the brain after systemic injection. It is
tempting to suggest that the failure of A-5,6
DTN to elicit the YE syndrome is evidence that
the responses are centrally nduced. Such a
conclusion is however premature n the absence of
evidence indicating whether A5,6-DTN possesses
dopamine autoreceptor activity r alternatively
whether it elicits yawning and penile erections
following intracerebral injection. There is
evidence that the YE syndrome is mediaed
centrally as domperidone, a specific peripherthy
acting dopamine antagonist, did not prevent
apomorphine-induced yawning and penile
erections. This result substantiates previous
findings by Benassi-Benelli et al. (1979) who
reported that penile erections induced by
apomorphine or NPA were not antagonised by
domperidone.
In addition to the drugs included in this
study, other agents are known to cause yawning
with or without an increase in penile erections.
For example, ACTH and related peptides will
induce a YE syndrome in animals although these
effects are not elicited on peripheral
injection. Glutamate diethyl ester, a glutamate
antagonist, injected i.p. has been reported to
cause yawning; its effects on penile erections
are not known. While these compounds represent a
possible source of false positives, they are at
present readily distinguishable chemically from
known dopamine agonists. On the other hand ACTH-
or glutamate antagonist-induced yawning may
involve a dopamine receptor.
The slight enhancing effect of SKF 38393 on
penile erections but with yawning not affected
suggests that the neuromechanisms mediating the
two responses may be separable. Not only do the
results obtained with physostigmine clearly
support such a hypothesis but we have also found
that naloxone inhibited apomorphine-induced
yawning but potentiated apomorphine-induced
penile erections (to be published). A similar
potentiation by naloxone of NPA-induced penile
erections was reported by Ferrari and Baggio
(1982). However, despite the indications that
the two responses can be separated, our studies
show that the elicitation of yawning accompanied
by penile erections may indicate the activation
of a particular class of dopamine
receptors.
-Berendsen
HG Androgenic influences on
apomorphine-induced yawning in rats Behavioral
and neural biology 1981; 33; 123-128
-Berendsen
HG, Gower AJ Opiate influences on
drug-induced yawning in the rat Behav Neural
Biol. 1981; 33; 1; 123-128
-Berendsen
HG ; AJ Gower Opiate-androgen interactions
in drug-induced yawning and penile erections in
the rats Neuroendocrinology 1986; 42;
185-1901
-Berendsen
H et al Involvement of 5-HT1c-receptors in
drug-induced penile erections in rats
Psychopharmacology 1990; 101; 57-61
-Gower
AJ Effects of acetylcholine agonists and
antagonists on yawning and analgesia in the rat
Europ J Pharmacology 1987; 139; 79-89
