- Penile erection and yawning are two
différent behavioral patterns that often
occur concomitantly in physiological and
experimental conditions. Studies from our and
other laboratories have shown that dopaminergic
agonists, such as apomorphine and oxytocin, are
among the most potent inducers of such a
symptomatology in male rats, and a neuronal
dopamine-oxylocin link occuring in the
paraventricular nucleus of the hypothalamus
(PVN), is supposed to have key role in the
expression of these behavioral patterns. As far
as the molecular mechanisms activated by
dopaminergic agonists and oxytocin
in the paraventricular nucleus are
concerned, calcium and pertussis toxin-sensitive
G proteins seem to be involved in the expression
of these behavioral patterns, because nanogram
amounts of the potent N-type calcium channel
blocker omega-conotoxin-GVIA or pertussis toxin
prevents the above symptomatology when injected
in the hypothalamic nucleus.
-
- We show here that the peripheral and central
administration of N-nitro-L-arginine methyl
ester (NAME) and N'-monomethyl-L-arginine
(NNINIA), inhibitors of nitric oxide (NO)
synthase, the enzyme responsible for the
formation of NO, a novel discovered transduction
messenger in the peripheral and central nervous
system, prevents apomorphine- and
oxytocin-induced penile erection and yawning.
[...]
-
- DISCUSSION
The present results show that the systemic as
well as the central administration of NAME or
NMMA, but not D-NMMA, prevent penile crection
and yawning induced by apomorphine and oxytocin.
The above effect seems to be caused by the
inhibition of NO synthase, because the potency
of these compounds in preventing penile erection
and yawning is parallel to their potency in
inhibiting the activity of this enzyme in brain.
The ability of NO synthase inhibitors to prevent
penile erection when given IV is in agreement
with recent studies showing that NO is a
physiological mediator of penile erection at the
level of the penile vasculature. Accordingly,
NAME and NMMA given IV were found to capable of
preventing penile erections induced by the
electrical stimulation of the cavernous nerve
(NAME was about 6 times more potent than NMMA).
Nevertheless, the ability of NAME and NMMA
when given into one of the lateral ventricles
to prevent penile erection and yawning induced
by apomorphine and oxytocin suggests that
central rather than peripheral NO synthase is
involved in the control of these behavioral
responses induced by apomorphine and
oxytocin. In agreement with this hypothesis,
both apomorphine and oxytocin act in the PVN to
induce penile erection and yawning, and this
nucleus bas been shown to contain NO
synthasecontaining neurons. Although the
neurotransmitters of these hypothalamic neurons
have not been yet identified, the results
suggest that oxytocin acts on neurons whose
activity is dependent from a normal level of NO.
Because NO stimulates soluble guanylate cyclase
by binding with high affinity to iron in the
heme of guanylyl cyclase, eliciting a
conformational changes that enhances the
catalytic activity of the enzyme, thus
increasing the concentration of cyclic guanosine
3',5' monophosphate (cGMP) in several tissues
such as macrophages, vascular smooth muscles,
and brain, it is tempting to speculate that a
decrease in the content of this second messenger
which, in turn, activate protein phosphorilation
by eGMP-dependent protein kinases, might be
responsible for the inhibition of oxytocin
responses by NO syntetase inhibitors. If the
above hypotesis were correct, one would suggest
that oxytocin is acting through the activation
of a cGMP-dependent mechanism secondary to an
increased calcium influx through the neuronal
membranes of the target cells. In agreement with
this hypothesis, oxytocin-induced penile
erection and yawning are prevented by calcium
channel blockers such as omega-conotoxin-GVIA. A
similar model has been proposed to explain the
blockade by NO synthase inhibitors of the
increase in cGMP induced by glutamate or
N-methyl-D-aspartate (NMDA) in cerebellar
slices. In this preparation, stimulation of the
ion channel-coupled NMDA glutamic acid receptor
subtype induces a calcium ion influx. Calcium
ions bind to calmodulin activating NO synthase
to produce NO, thereby stimulating guanylate
cyclase. Although the mechanism by means of
which cGMP might mediate penile erection and
yawning is unknown, the above interpretation can
be applied also to explain the inhibition by NO
synthase inhibitors of apomorphine-induced
penile erection and yawning, if one assumes that
apomorphine induces the above responses by
stimulating oxytocinergic transmission in the
PVN (see the Introduction section). However, the
possibility that NO synthase inhibitors act
before oxytocin in order Io inhibit apomorphine
responses cannot be ruled out at present, and
further studies are necessary to clarify this
point.
In conclusion, our results suggest that NO
plays a key role in the expression of yawning
and a primary sexual function such as penile
erection, not only in the periphery at the level
of the penile vasculature, but aiso in the
central nervous system.
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