The central administration of nanogram
amounts of oxytocin induces repeated episodes of
penile erection and yawning in male rats ). This
effect seems to be mediated by the stimulation
of specific uterine-type oxytocinergic
receptors, being induced by oxytocin analogs
with a potency that follows their oxytocic
potency and prevented by nonapeptide antagonists
with a rank order of potency that follows their
antioxytocic activity. These receptors are
probably located in the paraventricular nucleus
of the hypothalamus (PVN), since microinjection
studies have reveaIed this nucleus to be the
most sensitive brain area for the induction of
the above behavioral responses by oxytocin,
while its destruction causes an almost complete
prevention of oxytocin effect.
The involvement of uterine-type
oxytocinergic receptors in the expression of
oxytocin-induced penile erection and yawning
raises the possibility that oxytocin is acting
in the central nervous system to induce the
above responses by a mechanism similar to that
responsible for the induction of uterine
contraction. In the uterus oxytocin receptor
stimulation induces both calcium mobilization
and synthesis of prostaglandins, other potent
stimulants of the uterus which probably act
synergistically with oxytocin during
parturition. In order to verify whether or not
calcium and prostaglandins play a role in the
expression of oxytocin-induced penile erection
and yawning, we have studied the effect of
inhibitors of calcium channels and of
prostaglandin synthesis on oxytocin-induced
penile crection and yawning and the effect of
microinjection of calcium and prostaglandins in
the PVN on spontaneous penile erection and
yawning as well. [...]
DISCUSSION
The present results show that organic
calcium channel inhibitors prevent in a
dose-dependent manner penile erection and
yawning induced by oxytocin. Such effect of
calcium channel inhibitors seems to be central,
since it is observed not only after IP
administration of the drugs, but also after
their ICV injection. The finding suggests that
oxytocin exerts its effect on penile erection
and yawning by increasing calcium influx in some
neuronal population of the rat brain. Indeed,
verapamil, flunarizine, nifedipine, nimodipine
and nicardipine are thought to be rather
selective calcium channel inhibitors, although
they belong to different chemical classes and
differentially affect calcium channel
subtypes.
The prevention of penile erection and
yawning is observed at relatively high doses of
calcium channel inhibitors. The requirement of
such high doses probably reflects the presence
of a subtype of calcium channel in the central
nervous system different from that found in
cardiac and smooth muscle tissue, which makes
the nervous tissue poorly sensitive to the
action of these compounds. The slightly higher
potency of nimodipine and nicardipine might also
be due to the greater affinity of these
dihydropyridines for the nervous tissue than
that of the other dihydropyridine nifedipine,
the phenylalkylarnines (ie., verapamil) or the
diphenylpiperazines (i.e., flunarizine).
Accordingly, autoradiographic studies revealed
high density of binding sites for nitrendipine
in brain synaptosomes, which are not labeled by
verapamil or diltiazem.
However, the possibility that the prevention
of penile erection and yawning is due to
unspecific effects of calcium channel inhibitors
cannot be completely ruled out from the present
results. At high doses, in fact, these compounds
have been found able to inhibit not only calcium
channels, but also sodium and potassium channels
and to interact, at least in vitro, with central
and peripheral a2-adrenergic and muscarinic
receptors. However, it is unlikely that the
prevention of oxytocin effect is due to
adrenergic or muscarinic receptor blockade since
alpha2-adrenergic antagonists have a
facilitatory role on sexual activity and the
interaction with muscarinic receptors is seen
only at very high doses.
Despite the above possibility, further
support for a role of calcium in the expression
of penile erection and yawning induced by
oxytocin is provided by the finding that
elevation of calcium concentration in the PVN
region, the most sensitive brain area for the
induction of the above responses by oxytocin
induces a similar symptomatology. In contrast,
inhibition of prostaglandin synthesis by
indomethacin or by aspirin was unable to alter
oxytocin-induced penile erection and yawning,
suggesting that prostaglandins are not involved
in the expression of these behavioral responses.
Accordingly, microinjection of prostaglandins in
the PVN, unlike oxytocin or calcium gluconate,
was unable to induce penile erection and
yawning.
Taken together, the ability of calcium
channel inhibitors to prevent oxytocin-induced
penile erection and yawning and of calcium
microinjections in the PVN to induce an
oxytocin-like effect suggest that oxytocin
induces the above behavioral responses by acting
in the PVN by a mechanism similar to that
operating in the uterus or mammary gland.
Accordingly, oxytocin action on these peripheral
tissues is dependent on the presence of intra-
and extracellular calcium, but not of cyclic
adenosinemonophosphate (c-AMP), and calcium
channel inhibitors prevent oxytocin-induced
uterine contractions This correlates well with
our recent findings showing that uterine-type
oxytocin receptors are involved in the induction
of penile erection and yawning by oxytocin.
Indeed, the structure activity relationship of
oxytocin and related peptides for the induction
of the above behavioral responses was found to
be similar to that reported for the induction of
uterine contraction or milk ejection.
As to the mechanism by which oxytocin
mobilizes calcium to induce the above responses,
only some speculation is possible at present.
One possibility is that oxytocin activates
directly calcium channels or influences one of
the various biochemical systeins known to modify
calcium homeostasis, such as phosphoinositide
turnover, ATPase activity or calcium binding to
calmodulin-like proteins. Some of these
mechanisms have been reported to be operative in
the uterus, but have not been yet demonstrated
in brain. In particular, the data available so
far in the literature suggest that oxytocin,
unlike vasopressin, is unable to alter
phosphoinositide breakdown in brain tissue even
at relatively high doses. In spite of the lack
of biochemical correlates, electrophysiological
studies have shown that oxytocin is able to
activate several neuronal populations in
different rat brain areas including the
hypothalannic supraoptic nucleus and PVN, the
hippocampus and the dorsal motor nucleus of the
vagus nerve. Interestingly, in the PVN, where
oxytocin seems to act to induce penile erection
and yawning, oxytocin excites its own neurons
and this effect is strongly reduced in presence
of low calcium/high magnesium media, suggesting
the involvement of calcium influx in the above
responses.
In addition to oxytocin, other substances
induce repeated episodes of penile erection and
yawning in rats. Among them are dopaminornimetic
drugs, such as apomorphine. Recently, we have
provided experimental evidence showing that this
dopaminergic agonist induces these behavioral
responses by releasing oxytocin in the central
nervous system. Accordingly, apomorphine-induced
penile erection and yawning are prevented by
oxytocin receptor antagonists with a rank order
of potency that follows their antioxytocic
potency; the brain area most sensitive for the
induction of the above effects either by
oxytocin or apomorphine is the PVN; destruction
of oxytocinergic neurons within the brain and
spinal cord by electrolytic lesion of the PVN
abolishes apomorphine-induced responses. If the
above hypothesis were correct,
apomorphine-induced response would be
antagonized in a dose-dependent manner by
calcium channel inhibitors, as found for
oxytocin effect. Accordingly, we have found that
calcium channel inhibitors prevent
apomorphineinduced penile erection and
yawning.
In conclusion, although further studies are
necessary to clarify the mechanism responsible
for calcium mobilization, the present data
suggest that calcium is the second messenger
which mediates oxytocin-induced penile erection
and yawning.
