5-HT1a
receptor agonists prevent in rats the yawning
and penile erections induced by direct dopamine
agonists
Simon P, B Guardiola et al
Faculté
médecine et pharmacie de Rouen,
France
(+) S-20499, an amino chromane derivative
(8[-4[N-(5methoxychromane-3yl)N-propylaminobutylj
azaspiro [4-5] décane-7,9 dione),
is a full agonist of 5-H1a receptor for which it
displays a high affinity, in the 10(-10) M
range. Because most 5-HT1a agonists are also
active at the D2 dopamine receptor we have
investagated the possible activity of (+)
S-20499 on the dopaminergic system. For this
purpose binding studies were carried out. Since
the compound had significant affinity at both
receptors, the intrinsic activity (agonist or
antagonist?) was determined in mice by testing
the effect of the drug on body temperature;
since DA agonists are hypothermie in mice. The
observed hypothermia. combined with its
antagonism by the D2 antagonist haloperidol,
allowed the conclusion that the drug displayed,
like 8-OH-DPA, a D2 DA agonist activity.
It was expected therefore that its
administration at increasing doses would induce
yawning and penile erections but unexpectedly,
these were not observed. To explain this
discrepancy, the possible influence of the
5-HT1a agonist property on the expression of
these two behaviors which are modulated by the
stimulation of D2 DA receptors was examined in
this present paper. [...]
Discussion : Beside its high affinity
for the 5-HT1a receptor, ( + ) S-20499 displays
a notable affinity for dopamine D2 receptors.
(+) S-20499 induces in mice a hypothermic effect
which was reversed by the D2 dopamine receptor
antagonist haloperidol, but not by the 5-HT,1a
antagonist tertatolol. This indicates an agonist
property of (+) S-20499 for the D2 dopamine
receptors.
Therefore low doses of (+) S-20499 would
be expected to induce yawns and penile erections
in rats, whereas high doses would have
suppressed these behaviors, since such a
biphasic effect is characteristic of direct D2
dopamine receptors agonists (Protais
et al. 1983). Yawns and penile erections are
claimed to result from the stimulation of DA
autoreceptors, with a consequent decrease in
dopaminergic transmission. At high doses of DA
agonists these effects disappear simultaneously
as the restoration of an apparent dopaminergic
tone because of the post-synaptic D2 receptors
stimulation. Neither yawning nor penile
erections were in fact observed after
administration of (+) S-20499, over a wide range
of doses, in spite of its D2 dopamine agonist
activity. Since the drug displays a 100 fold
higher affinity for 5-HT1a receptors than for D2
dopamine receptors, it seemed possible that this
property might account for this unexpected lack
of yawning and penile erections.
This hypothesis was apparently verified since
(+) S-20499, together with two other reference
5-HT1a receptor agonists 8-OH-DPAT and buspirone
dose dependently inhibited apomorphine-induced
yawning and penile erections. The prevention by
stimulation of 5-HT1a receptors of yawning and
penile erections induced by DA agonists is also
supported by the observation that blocking
5-HTIa receptors by tertatolol restored the
typical effect of D2 agonists to ( + )S-20499.
Although the three tested drugs (buspirone,
8-OH-DPAT and (+) S-20499) are 5-HT, agonists,
one may speculate whether any other common
property might account for the antagonism of the
apomorphine- induced penile erections and yawns.
For instance, an antimuscarinic property could
lead to such an effect.
Indeed, concerning yawning, a cholinergic
link has been shown. This explanation cannot
apply, at least for ( + ) S-20499, since at 2
mg/kg dose (fully effective versus apomorphine
effects) the drug did not reduce the
hypothermic, akinetic or tremorogenic effects of
oxotremorine (0.5 mg/kg) in mice (not
shown).
On the other hand, it should be remembered
that buspirone, in addition to its 5-HT1a
agonist activity, also displays a D2 dopamine
antagonist activity. Concerning penile
erections, for which such a cholinergic link has
not been shown, serotonergic transmissions seem
to have a complex modulatory effect, since
Berendsen et al. (1990) have reported that
5-HT1c agonists induce penile erections.
In conclusion, it appears that in
addition to its potent 5-HT1a agonist property,
(+) S-20499 displays a significant D2 agonist
property, and that the stimulation of 5-HT1a
receptors oppose the action of D2 dopamine
receptors with regard to yawning and penile
erections. A recent microdialysis study by
Benloucif and Galloway (1991) indicated that
8-OH-DPAT perfused in rat striatum increased DA
release. This might indicate a mechanism of
action of 5-HT1a agonists, which could oppose to
the inhibition of DA release elicited by low
doses of D2 agonists. However, this interaction
seen at the striatal level, may not occur in the
brain area(s) where DA transmission modulates
yawning and penile erections. Finally, one may
wonder whether such interactions might extend to
various other DA dependent behaviors. The only
partial response presently known concerns the
stereotyped climbing elicited by apomorphine on
which (+) S-20499 was ineffective
(unpublished).
