- Introduction : Penile erection and
yawning are two different behavioural patterns
that often occur concomitantly in physiological
and experimental conditions.
- Although the importance of penile erection
in reproduction does not need to be stressed,
the response can also be observed in other
contexts, such as manipulation of the genitalia,
erotic fantasies and sleep in humans. Depending
on the context in which penile erection occurs,
different neural and/or humoral mechanisms may
participate in its regulation . The
physiological significance of yawning is less
clear: the act alone or associated with
stretching is considered an ancestral vestige,
surviving through evolution, that subserves the
purpose of arousal, although its role is not
entirely certain.
- Among substances that induce both these
responses the best known are dopamine receptor
agonists (i.e. apomorphine), oxytocin,
adrenocorticotropin and related peptides, N
methyl-D-aspartic acid and serotonin receptor
agonists that act mainly on the serotoninj,
receptor subtype. Interestingly, the
paraventricular nucleus of the hypothalamus
(PVN) seems to play a key role in these
behavioural responses when they are induced by
the dopamine receptor agonists,
N-methyl-D-aspartic acid and oxytocin, but not
when they are induced by adrenocorticotropin or
serotonin receptor agonists.
- Indeed, the former, but not the latter
compounds induce penile erection and yawning
when injected in the PVN. These responses are
apparently mediated by the activation of
oxytocinergic transmission, since they are
prevented by the central administration of
oxytocin receptor antagonists and by
electrolytic lesions of the PVN that induce an
almost complete depletion of oxytocin content in
extra-hypothalamic brain areas and spinal cord
However, since PVN lesions do not prevent penile
erection and yawning induced by
adrenocorticotropin or penile reflexes and
erections in copula, additional neuronal
pathways must be involved in the contro, of
these behavioural responses.
- Recently we found that the putative
neurotransmitter/neuromodulator nitric oxide
(NO) is involved in penile erection and yawning
induced by apomorphine, oxytocin,
N-methylD-aspartic acid and serotonin 1c
agonists. In particular, the above compounds
(except serotonin 1c agonists) seem to induce
these behavioural responses by activating NO
synthase in the PVN, which in turn leads to the
activation of central oxytocinergic
transmission. Accordingly, NO synthase
inhibitors prevent apomorphine-,
N-methylD-aspartic acid- and oxytocin-induced
penile erection and yawning when injected in the
PVN, while NO donors injected into the PVN
induce penile erection and yawning that are
indistinguishable from those induced by the NO
synthase activators and are prevented by the
injection of oxytocin receptor antagonist
d(CH2)5Tyr(Me)-Orn 8 -vasotocin into the lateral
ventricles.
- In order to provide further support for a
role of paraventricular NO in penile erection
and yawning induced by apomorphine, we studied
the effect of a low dose of apomorphine and
other dopamine receptor agonists on the
production of NO in the PVN in vivo. This was
achieved by measuring the concentration of the
reaction products of newly formed NO with 02,
N02- and N03, which provides an indirect but
reliable indicator of NO production in vivo, in
the dialysate collected from a vertical
rnicrodialysis probe implanted in the PVN.
[...]
-
- Discussion
- The present results show that a dose of
apomorphine that induced penile erection and
yawning increased basal N02- and, to a lesser
extent, N03- concentration in the PVN dialysate
of male rats. A similar increase of N02-
concentration was found with LY 171555, a
selective D2 receptor agonist that, like
apomorphine, induced penile erection and
yawning, but not with SKF 38393, a D1 receptor
agonist that was unable to induce these
behavioural responses. These results are in line
with the hypothesis that dopamine receptor
agonists induce penile erection and yawning by
activating D2 receptors in the PVN and that the
stimulation of these receptors leads to the
activation of NO synthase in this hypothalamic
nucleus. Accordingly, L-sulpiride, a dopamine
receptor antagonist that acts mainly on D2
receptors, prevented not only penile erection
and yawning but also the NO2- concentration
increase induced by apomorphine in the PVN
dialysate.
- The results also confirim previous studies
showing that SCH 23390, a D1 receptor
antagonist, was able to prevent penile erection
and yawning induced by D2 receptor agonists.
Hence, by showing that SCH 23390, unlike
haloperidol or Lsulpiride, is unable to prevent
the increase in N02- concentration induced by
apomorphine in the PVN dialysate, despite its
efficacy in preventing penile erection and
yawning, the present results suggest that D1
receptors control these behavioural responses by
a mechanism either not involving paraventricular
NO synthase or acting in brain areas different
from the PVN.
- As far as the possibility that dopamine
agonists stimulate NO synthase in the PVN is
concerned, it is noteworthy that this
hypothalamic nucleus is one of the brain areas
richest in NO synthase and that the enzyme is
present in the cell bodies of oxytocinergic
neurons.
- Furthermore, the increased concentrations of
N02- and N03- induced in the PVN dialysate by
these agents would reflect almost exclusively an
increased conversion of L-arginine to NO that is
in turn oxidized mainly to N02- and, to a lesser
extent, N03- as found in other biological fluids
not containing blood cells.
- In agreement with the above hypothesis,
NG-nitro-L-arginine methyl ester, a potent
inhibitor of NO synthase given i.c.v. prevented
both apomorphine-induced increase of N02-
concentration and penile erection and yawning.
Conversely, the apomorphine-induced increase in
N02- concentration was also prevented by
haemoglobin, a potent NO scavenger . However,
this interpretation is complicated by the
inability of haemoglobin to prevent
apomorphine-induced penile erection and yawning.
Such apparent discrepancy can be explained by
assuming that NO formed by apomorphine
stimulation of dopamine receptors in the PVN
acts as an intracellular messenger in the
neurons in which is formed rather than an
extracellular transmitter. In fact, due to, its
high molecular weight haemoglobin is unable to
cross cellular membranes and would therefore be
expected to scavenge extracellular rather than
intracellular NO-although this does not rule out
the possibility that NO released from the cells
in which it is produced acts as an extracellular
transmitter and is involved for instance in
other hypothalarnic responses induced by
apomorphine.
- The present results show also that
d(CH2)5Tyr(Me)-Orn 8-vasotocin, a potent
Oxytocin receptor antagonist, has no effect on
the apomorphine-induced increase of N02
concentration, despite its ability to prevent
penile erection and yawning. This apparent
discrepancy may be explained by the inability of
oxytocin receptor antagonists to prevent
apomorphine-induced penile erection and yawning
when injected in the PVN (see Argiolas and
Melis, 1995). In fact, if one assumes that
apomorphine stimulates PVN D2 receptors to
activate PVN NO synthase and oxytocinergic
neurons that in tum release oxytocin in brain
areas distant from the PVN to induce penile
erection and yawning, the oxytocin receptor
antagonist would be expected to act at the sites
where oxytocin is released, i.e. after NO
formation, to prevent these responses. The
mechanism by which NO formed by dopamine
receptor stimulation leads to the activation of
PVN oxytocinergic neurons to mediate penile
erection and yawning is unknown. One possibility
is that NO increases the firing rate of
oxytocinergic neurons and/or oxytocin synthesis.
Indeed, the dose of apomorphine used in this
study was shown to increase oxytocin
concentration in the hippocampus as well as in
blood of male rats.
- An similar interpretation can also explain
the ability of methylene blue to prevent penile
erection and yawning but not the
N02concentration increase induced by
apomorphine. Indeed, methylene blue prevents
apomorphine-induced penile erection and yawning
when given i.c.v. but not in the PVN. Thus it is
likely that methylene blue, like oxytocin
receptor antagonists, acts at sites distant from
the PVN to prevent the behavioural responses of
apomorphine. Since methylene blue is an
inhibitor of guanylate cyclase, one of the best
known targets of NO, its inability to prevent
the apomorphine-induced increase in N02-
concentration provides further evidence that NO
acts in the PVN to control penile erection and
yawning by a mechanism not related to the
activation of guanylate cyclase. Accordingly,
the injection of a stable cyclic guanosine 3',5'
monophosphate analogue (e.g. 8-bromo-cyclic
guanosine 3',5' monophosphate) into the PVN was
not able to induce penile erection or yawning.
The above results do not, however, rule out the
possibility that guanylate cyclic is involved in
the control of these behavioural responses in
distant from the PVN
- In conclusion, the present study
shows that dopamine agonist at doses that induce
penile erection and yawning by activating
oxytocinergic transmission, increase the
concentration of N02N03 in the PVN dialysate
through the stimulation of D2 recept Since NO2-
and N03- concentration in extracellular fluids
is a reliable index of the activity of NO
synthase, the results provide further evidence
that NO plays an important role in the control
of the behavioural responses at the level of
this hypothalamic nucleus.
Influence
of sildenafil on central dopamine-mediated
behaviour in male rats F Ferrari
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