Introduction : penile erection and
yawning are two distinct behavioural patterns
that often occur concomitantly under certain
physiological and experimental conditions. Among
substances that induce both penile erection and
yawning, dopamine receptor agonists (e.g.
apomorphine), oxytocin and adrenocorticotropin
(ACTH) are certainly the most widely known.
While several lines of experimental evidence
suggest that a dopamine-oxytocin link plays a
key role in the expression of these behavioural
responses, ACTH and related peptides seem to act
through a mechanism(s) not involving central
dopamine or oxytocin:
both penile erection and yawning are induced
by apomorphine and by oxytocin injected in the
paraventricular nucleus of the
hypothalamus;
apomorphine and oxytocin responses are
prevented either by oxytocin receptor
antagonists or by electrolytic lesions of the
paraventricular nucleus that deplete oxytocin in
the central nervous system;
the ACTH effect is not prevented either by
oxytocin receptor antagonists or by electrolytic
lesions of the paraventricular nucleus.
Recent experimental evidence has shown that
penile erection and yawning can also be induced
in male rats by drugs that modify serotonin
(5-hydroxytryptamine, 5-HT) transmission, in
particular, 5-HT receptor agonists that act on
the 5-HT1c receptor subtype. It has also been
shown that the effect of these drugs on penile
erection is often paralleled by increased
oxytocin release in plasma. This latter effect
seems more related to the stimulation of 5-HT1a
and/or 5-HT2 receptors although a role of 5-HT1c
receptors cannot be ruled out. In agreement with
this hypothesis, the paraventricular nucleus
receives a dense 5-HT innervation originating
from the raphe nuclei of the medulla oblongata.
The above results led to the suggestion that
penile erection induced by these drugs is
mediated by an increased oxytocinergic
transmission.
In order to test this hypothesis, we
studied: (1) the effect of dopamine and oxytocin
receptor antagonists on 5-HT1c receptor
agonist-induced penile erection and yawning; and
(2) the effect of 5-HT receptor antagonists on
apomorphine- and oxytocin-induced penile
erection and yawning. [...]
Discussion : the present results
confirm and extend previous findings showing
that m-CPP and TMFPP, but not 8-OH-DPAT, induce
penile erection and yawning. In particular,
although previous reports were focussed mainly
on the ability of these compounds to induce
penile erection, our results showed that they
are as effective in inducing yawning.
Indeed both drugs induced yawning according
to a U inverted bell-shaped dose-response curve
as found with penile erection. The prevention of
m-CPP- and TFMPP-induced penile erection and
yawning by mianserin and ritanserin with a
potency that follows their potency for blocking
5-HT1c receptors together with the inability of
8-OH-DPAT, a selective agonist of 5-HT1a
receptors, to induce these responses are in
agreement with the suggested key role of the
5-HT1c receptor subtype in these behavioural
responses. However, the failure of the potent
oxytocin receptor antagonist,
[d(CH2),Tyr(Me)2 Orn8-vasotocin, to prevent
such responses does not support the hypothesis
that 5-HT1c receptor agonist-induced penile
erection is mediated by increased central
oxytocinergic transmission.
This is in contrast with the ability of 5-HT
receptor agonists to increase plasma oxytocin
concentration (that is to activate magnocellular
oxytocinergic neurons), but is favoured by at
least three lines of experimental evidence. The
first is that the 5-HT receptor agonist-induced
increase of plasma oxytocin is mediated mainly
by the stimulation of 5-HT1a and 5-HT2 receptors
rather than 5-HT1c receptors located in the
hypothalamic supraoptic and paraventricular
nuclei. The second is that 8-OH-DPAT, despite
its ability to increase plasma oxytocin
concentration by stimulating 5-HT1a receptors,
not only does not induce penile erection and
yawning but also prevents m-CPP-induced penile
erection.
Although the mechanisms mediating these
8-OH-DPAT responses are unknown, this suggests
that increased plasma oxytocin concentrations do
not always reflect an increased
extrahypothalamic oxytocinergic function and
that 5-HT1a and 5-HT1c receptors might have
different roles in the expression of penile
erection. The third piece of evidence is that
m-CPP and TFMPP do not induce penile erection
and yawning when injected in the paraventricular
nucleus, in contrast to apomorphine and
oxytocin.
This also suggests that ascending
serotoninergic projections from raphe nuclei to
the paraventricular nucleus are not involved in
the expression of these m-CPP- and TFMPP-induced
responses. Likewise, the failure of the blockade
of dopamine receptors by haloperidol to modify
m-CPPand TFMPP-induced penile erection and
yawning rules out the possibility that these
responses are mediated by increased central
dopaminergic activity. These results are in line
with the inability of spiperone to prevent
m-CPP-induced penile erection in male rats, but
contrast with previous findings by the same
group showing that m-CPP-induced yawning was
prevented by haloperidol. The reason for this
discrepancy is unknown, since similar times and
doses of haloperidol and m-CPP were used in both
studies, although the possibility cannot be
ruled out that it is related to other different
experimental conditions.
All together, the results discussed above
suggest that 5-HT1c receptor agonists induce
penile erection and yawning by activating
neuronal circuits different from those activated
by dopamine receptor agonists and/or
oxytocin. However, the above results do not
rule out the possibility that 5-HT1c receptor
agonists act at sites located after dopamine and
oxytocin in the cascade of neuronal events
mediating penile erection and yawning. The
reduction of penile erection by mianserin and
ritanserin is in agreement with this hypothesis
at least for this behavioural response. This
also raises the possibility that a neuronal
dopamine-oxytocin-5-HT link is involved in the
control of penile erection.
Interestingly, two pathways that might be
candidates for such a link, one, oxytocinergic
originating in the paraventricular nucleus, and
another, serotoninergic originating in the
nucleus paragigantocellularis of the ventral
medulla (e.g. the pars alpha of the
gigantocellular reticular nucleus of the ventral
medulla, have been recently identified. In
particular the former structure facilitates and
the latter inhibits penile erection, but both
send projections to the lumbar spinal cord in
the region of the spinal nucleus of the
bulbocavernosus. It is consistent with this
possibility that
electrolytic lesions of the paraventricular
nucleus, that destroy all central oxytocinergic
projections including those reaching the spinal
cord abolish apomorphine- and oxytocin-induced
penile erection
electrolytic lesions of the nucleus
paragigantocellularis facilitate penile reflexes
and copulatory behaviour in male rats
drugs that enhance 5-HT transmission,
especially 5-HT2 receptor agonists, impair these
sexual responses
Since 5-HT1c receptor agonists injected in
the paraventricular nucleus do not induce penile
erection whereas mianserin and ritanserin reduce
it when it is induced by apomorphine or
oxytocin, it is tempting to speculate that the
paraventricular nucleus-spinal oxytocinergic
pathway induces the sexual response by favouring
the stimulation of 5-HT1c receptors in the
spinal nucleus of the bulbocavernosus. These
receptors might be located post-synaptically
because penile erection is also induced by 5-HT
releasers and uptake blocker.
Alternatively the stimulation of these
spinal 5-HT1c receptors might be achieved by a
paraventricular nucleus-medullary oxytocinergic
pathway controlling the spinal serotoninergic
pathway in the ventral medulla. Accordingly,
several nuclei containing oxytocinergic
innervation originating in the paraventricular
nucleus, i.e. the nucleus ambiguus, the lateral
reticular nucleus and the olivas, are located
close to the nucleus paragigantocellularis.
Despite the possibility discussed above that
a dopamine-oxytocin-5-HT link is involved in the
control of penile erection, the failure of
5-HT1c receptor antagonists to prevent
apomorphine- or oxytocin-induced yawning
suggests that 5-HT1c receptor agonists induce
this response by means of a mechanism not
involving dopamine or oxytocin, thereby
excluding the involvement of a
dopamine-oxytocin-5-HT link in the expression of
yawning. The finding also provides additional
evidence that penile erection and yawning, that
often appear concomitantly in different
experimental and pharmacological conditions, can
be differentially regulated.
The best known evidence for different
regulation of apomorphine- and oxytocin-induced
penile erection and yawning is perhaps provided
by the effects of sex steroids on these
responses in hypophysectomized and castrated
rats:
hypophysectomy and castration abolish both
responses
testosterone restores penile erection but
not yawning in hypophysectomized and castrated
male rats
estradiol benzoate restores yawning but not
penile erection in castrated male rats,
5a-dihydrotestosterone restores
apomorphine-induced yawning but not penile
erection in castrated male rats. However, this
latter finding has been recently questioned and
is in contrast with the above mentioned
inability of testosterone to restore yawning in
castrated male rats.
In conclusion, the presentt results show
that penile erection and yawning induced by
5-HT1c receptor agonists is not mediated by
increased central dopaminergic or oxytocinergic
transmission, and suggest the existence of a
dopamine-oxytocin-5-HT link involved in the
control of penile erection and not necessarily
of yawning in male rats.
