Involvement
of 5-HT 1c-receptors in drug-induced penile
erections in rats
H Berendsen, F Jenck, C Broekkamp
Department of CNS
Pharmacology, Organon International, The
Netherlands
Penile erections (PE) can be induced in rats
by the serotonin (5-HT)-releasing compound
fenfluramine, 5-HT reuptake inhibitors, the 5-HT
agonist mCPP, the 5-HT agonist quipazine in
5-HT2 antagonist-pretreated rats and by
5-hydroxytryptophan (5HTP) in rats pretreated
with a monoamine oxydase inhibitor and a
peripheral decarboxylase inhibitor. Fenfluramine
and mCPP also induce PE in non-human primates.
Previously we have investigated the pharmacology
of induction of penile erections and suggested
that it is probably mediated by the 5-HT 1b
receptor. However, recently Pazos et al. (1985)
and later Heuring and Peroutka (1987) showed
that, in the 5-HT1b binding test, 5-HT1b and
perhaps 5-HT1c sites were also labelled. The
affinity of various compounds for the 5-HT,
receptor has now been described and a number of
reference compounds including both mCPP and
quipazine appear to bind more strongly to the
5-HT1c, receptor than to one of the other 5-HT
receptor subtypes. These developments
necessitate a re-evaluation of the
interpretation of PE induction. In this paper
the effect of a number of 5-HT agonists TFMPP,
MK 212, DOl and of the 5-HT antagonists
metergoline, cyproheptadine, mesulergine,
mianserin and ritanserin, which all share potent
5-HT1c activity, on PE are described. The
results strongly suggest that the 5-HT1c rather
than the 5-HT,1b receptors are involved in the
induction of PE by 5-HT compounds.
[...]
Discussion
Although mCPP and TFMPP have been claimed
before to have some selectivity for the 5-HT1b
receptor, there is now in vitro as well as in
vivo evidence that these drugs also have potent
5-HT1c affinity. Both compounds induce PE. MK
212, which has very poor affinity for the 5-HT1b
receptor but binds more potently to the 5-HT1c
receptor, also induced PE, whereas the recently
described selective 5-HT1b agonist CGS 12066 B
was ineffective in this respect. Therefore it
seems that the 5-HT1c rather than the 5HT1b
receptors are mediating the induction of PE.
This is further supported by the effects
obtained with DOl which binds potently to the
5-HT2 and 5-HT1c and only weakly to the 5-HT1a
and 5-HT1b receptors; DOl induces PE after
blockade of the 5-HT2 receptors with spiperone
or pirenperone, indicating that its 5-HT1c
properties were probably responsible for its
PE-inducing effect. The 5-HT antagonists
metergoline, cyproheptadine, mesulergine,
mianserin and ritanserin potently inhibited
mCPP-induced PE. These compounds have high
affinity for the 5-HT1c and 5-HT2 receptor in
common. Ketanserin, which has a somewhat lower
affinity for the 5-HT1c receptor, also less
potently antagonized mCPP-induced PE, whereas
spiperone, which hardly binds to the 5HT1c
receptor, but strongly to the 5-HT1a, 5-HT2 and
dopamine receptors, did not affect mCPP-induced
PE up to 0.46 mg/kg. At higher doses there may
be some effect, but these doses also induce
catalepsy. This suggests that blockade of the
5-HT1c receptor might be the most probable
explanation for the PE-inhibiting effect of the
5-HT antagonists.
An influence of 5-HT2 receptor activation or
blockade on both induction and inhibition of PE
cannot be excluded: DOl only induced PE after
blockade of the 5-HT2 receptor. The headshakes
which are thought to be the result of 5-HT2
receptor activation disappear after blocking the
5-HT2 receptor. It has been reported before that
quipazine also induced more PE in 5-HT2
antagonist pretreated rats. The influence of the
5-HT2 receptor may also explain why the effect
of MK 212 on PE is stronger than those of mCPP
or TFMPP, whereas the latter two compounds show
a higher affinity for the 5-HT, receptor than
MK212. If selectivity ratios for 5-HT1c versus
5-HT2 receptors are calculated then the sequence
for 5-HT, selectivity is MK
212>mCPP>TFMPP> quipazine> DOI and
this is also the sequence of potency to induce
PE. When the selectivity ratios for the 5-HT1c
versus 5-HT2 receptors of the antagonists are
calculated, then their selectivity for the
5-HT1c receptor is also closely parallel to
their potency to antagonise the mCPP-induced PE.
This suggests that 5-HT2 agonistic properties
prevent or counteract induction of PE and that
concomitant 5-HT2 antagonistic properties makes
the antagonist less effective. Indeed
DOl-induced PE in rats pretreated with a 5HT2
antagonist and at 2.2 mg/kg some antagonism of
mCPP-induced PE was seen. Interaction studies
have also been done with the 5-HT1a agonist
8-OH-DPAT and the mixed 5-HT1a/5-HT2 agonist
5MeODMT. Both compounds potently antagonise
mCPP-induced PE, indicating that 5-HT1a receptor
activation interferes with expression of 5-HT1c
receptor activation. Flat body posture induced
by these compounds could possibly influence
induction of PE but this cannot explain the
disappearance of PE by 8-OH-DPAT and 5MeODMT.
These drugs inhibit PE already at doses at which
flat body posture was not yet seen.
This functional interplay of the 5-HT1c
receptor subtypes has been seen before in other
experiments: mCPP and DOl prevented induction of
lower lip retraction by 8-OH-DPAT and
antagonised 8-OH-DPAT-induced hypoactivity and
hypothermia. A similar functional interplay of
the 5-HT1c receptor with the 5-HT1b receptor is
less likely, since simultaneous injection of
mCPP with the purported selective 5-HT1b agonist
CGS 12066 B did not change the effect of
mCPP.
The lack of effect of spiperone on
mCPP-induced PE excludes a role for dopamine
receptors. In agreement with this, it was
previously found that haloperidol at doses which
block yawning and penile erections induced by
the dopamine receptor agonist apomorphine did
not block mCPP-induced PE.
A role for the 5-HT3 receptors is not
likely, since GR 38032 F, a 5-HT3 antagonist,
had no effect on mCPP-induced PE. A functional
interplay with 5-HT1c and 5-HT3 receptors as
seen for the 5-HT1c with the 5-HT1a and 5-HT2
receptors cannot be excluded as yet, since a
selective 5-HT3 agonist is not available to
date. Induction of PE is not the only
consequence of activation of 5-HT1c receptors,
since it was found that mCPP- and TFMPP-induced
hypoactivity and hypophagia are probably also
5-HT1c receptor mediated effects. Our data
support the suggestion that the 5-HT1c receptors
play an important role in the control of
behaviour. The finding that 5-HT releasers and
5-HT uptake inhibitors induce PE further
indicates a postsynaptic location of the
responsible 5-HT1c receptors. A further
implication of these findings is that the 5-HT1c
receptors should be studied in the context of
depression. The putatively 5-HT1c receptors
mediated penile erections are not only induced
by the 5-HT uptake inhibitors but also by mCPP
the main metabolite of the antidepressant
compound trazodone and 5HTP. The 5-HT1c receptor
could very well be the common point of action
for these antidepressants.
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HG ; AJ Gower Opiate-androgen interactions
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H et al Involvement of 5-HT1c-receptors in
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AJ Effects of acetylcholine agonists and
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