Penile erection and yawning are two
different behavioral patterns that often occur
concomitantly in physiological and experimental
conditions. Oxytocin and apomorphine are among
the most potent substances able to induce penile
erection and yawning discovered so far and a
neuronal dopamine-oxytocin link in the
paraventricular nucleus of the hypothalamus
(PVN) seems to be involved in the induction of
these behavioral responses. As far as the
molecular mechanism by means of which
apomorphine and oxytocin induce these behavioral
effects is concerned, calcium and pertussis
toxin-sensitive G proteins seem to be involved,
because nanograrn amounts of the potent N-type
calcium channel blocker omega-conotoxin-GVIA or
of pertussis toxin prevent the above
symptomatology when injected in the PVN.
Recently we found that both peripheral and
central administration of inhibitors of nitric
oxide (NO) synthase, the enzyme responsible for
the formation of NO, prevent apomorphine- and
oxytocin-induced penile erection and yawning,
suggesting that this novel discovered
transduction messenger is also involved in the
control of these responses induced by
apomorphine and oxytocin. To further
characterize the role of NO in the control of
these responses, we studied the effect of the
microinjection of Ng-nitro-L-arginine methyl
ester (NAME), one of the most potent inhibitors
of NO synthase available so far, in different
brain areas on apomorphine- and oxytocin-induced
penile erection and yawning. Moreover, because
NO is supposed to act by stimulating guanylate
cyclase to produce cyclic guanosine 3',5'
monophosphate (cGMP), the effect of the central
microinjection of methylene blue, an inhibitor
of guanylate cyclase on apomorphine and
oxytocin-induced penile erection and yawning was
also studied. [...]
Discussion : The present resuits show
that the PVN is a brain site where NO synthase
inhibitors act to antagonize penile erection and
yawning induced by apomorphine or oxytocin. In
agreement with this hypothesis, the PVN is one
of the most rich brain areas containing NO
synthase-immunostaining neurons. This confirms
and extends previous results showing that
central NO is involved in the control of these
behavioral responses. In particular, the ability
of NAME to prevent penile erection when injected
in the PVN not only suggests that this novel
neurotransmitter is involved in the control of
this primary sexual function, but also, provides
further evidence for a major role of this
hypothalamic nucleus in the control of sexual
functions strictly related to the consummatory
phase of sexual behavior, ie., penile erection,
penile reflexes, and seminal emission.
The mechanism by which NAME acts in the PVN
to prevent penile erection and yawning is
unknown, and only some speculation is possible
at present. If one assumes that apomorphine
induces these responses by activating
oxytocinergic neurons in the PVN (see
introductory paragraphs), NAME might act by
preventing the activation of oxytocinergic
transmission.
In this respect, it is pertinent to recall
that apomorphine and oxytocin effects seem to be
mediated by an increase in calcium ion influx.
As already suggested for the NMDA
receptorcoupled calcium channel, calcium ions
might bind to calmodulin activating in turn NO
synthase to produce NO that activates guanylate
cyclase to increase cGMP production. If this
hypothesis were correct, NO would be considered
either as a second messenger, like calcium ions,
or a neurotransmitter itself that mediates
penile erection and yawning induced by
apomorphine and oxytocin. In agreement with the
above hypothesis, oxytocinergic neurons, when
activated by apomorphine or oxytocin itself
(see, should produce NO that might be released
cither by neuronal cell bodies and/or nerve
endings to act as a neurotransmitter activating
in turn the production of cGMP in target cells
or might act intracellularly as a second
messenger.
A neurotransmitter role of NO at sites
distant from the PVN is favored by the results
obtained with methylene blue, an inhibitor of
guanylate cyclase in several tissues, ie.,
platelets and vascular smooth muscles. Indeed,
methylene blue is unable to prevent penile
erection and yawning induced by apomorphine and
oxytocin when injected in the PVN, but is fully
active when injected ICV. This implies that cGMP
is involved in the effects of apomorphine and
oxytocin in some yet undiscovered brain area.
This explanation should be considered with
caution, because it was recently reported that
methylene blue can inhibit directly NO synthase
rather than guanylate cyclase. However, the
inability of methylene blue, unlike NAME, to
prevent penile erection and yawning when
injected in the PVN does not support such
possibility in our experimental conditions.
On the other hand, the ineffectiveness of
methylene blue injected in the PVN might
indicate that NO released by oxytocinergic cell
bodies in the PVN influences the expression of
penile erection and yawning by acting with a
mechanism not related to the activation of
guanylate cyclase, that is, by a
cGMP-independent mechanisin. NO infact might
interact with numerous other enzymes that, like
guanylate cyclase, bind metal ions such as iron,
as described for instance in fibroblasts. The
identification of the brain area in which the
inhibition of guanylate cyclase by methylene
blue or other inhibitors prevents apomorphine
and oxytocin responses will clarify this
point.
The above interpretations are in line with
the existence of a neuronal dopamine-oxytocin
link that controls these behavioral responses,
in particular, with previous findings showing
that apomorphine effect on penile erection and
yawning are prevented by oxytocin antagonists
given ICV but not injected into the PVN.
However, the prescrit results do not rule out
the possibility that NAME induces its effects by
acting in the PVN at targets different from the
cell bodies of parvocellular oxytocinergic
neurons that send their projections to several
brain areas. Indeed, to our knowledge, it is
unknown whether these oxytocinergic neurons
contain NO synthase or not, although the
coexistence of the enzyme with vasopressin in
magnocellular neurons has been recently
reported.
In conclusion, the present results suggest
that NO via a cGMP-depenilent mechanism is
involved in the control of penile erection and
yawning induced by apomorphine or oxytocin.
