Activation of
gamma-aminobutyric acid(A) receptors in the
paraventricular nucleus of the hypothalamus
reduces apomorphine-, N-methyl-D-aspartic acid-
and oxytocin-induced penile erection and yawning
in male rats
Penile erection and yawning are two
different behavioral patterns that often occur
concomitantly in different experimental and
physiological conditions. While the importance
of penile erection in mammalian reproduction
does not need to be stressed, it is pertinent to
recall that yawning is considered an ancestral
vestige that subserves the purposal of arousal,
although its role is far from being
clarified.
Among substances that induce both penile
erection and yawning in male rats, the best
known are dopamine receptor agonists, such as
apomorphine, the neurohypophyseal peptide
oxytocin, N-methyl-D-aspartic acid (NMDA), a
selective agonist of the excitatory amino acid
NMDA receptor subtype, and adrenocorticotropic
hormone (ACTH) - melanocyte stimulating hormone
(MSH) peptides. Apomorphine, NMDA and oxytocin
induce penile erection and yawning when injected
into the paraventricular nucleus of the
hypothalamus (PVN), apparently by activating
parvocellular oxytocinergic neurons originating
in the PVN and projecting to extra-hypothalamic
brain areas (e.g. the hippocampus, the medulla
oblongata and the spinal cord), while ACTH-MSH
peptides induce the above responses by acting
with a different mechanism. The induction of
penile erection and yawning by the above
substances is secondary to the activation of
nitric oxide synthase activity in the PVN,
possibly in the cell bodies of oxytocinergic
neurons mediating penile erection and yawning.
Accordingly, nitric oxide production is
increased in the PVN by doses of apomorphine,
oxytocin or NMDA that induce penile erection and
yawning.
Immunocytochernical and electrophysiological
studies show that paraventricular magnocellular
and parvocellular oxytocinergic neurons are
under inhibitory GABAergic control. Accordingly,
gamma-aminobutyric acid (GABA) synapses impinge
on the cell bodies of oxytocinergic neurons, and
GABA agonists decrease oxytocinergic
transmission in several circumstances. The
major ty of these inhibitory synapses belong to
GABAergic neurons originating mainly in the
perinuclear region that surrounds the PVN,
although the presence of intraparaventricular
GABAergic neurons cannot be ruled out. The
presence of GABAergic synapses impinging on
oxytocinergic neurons raises the possibility
that GABAergic agents might influence penile
erection and yawning, at the PVN level.
To test this hypothesis we studied the
effect of muscimol, an agonist of the GABAA
receptor, and baclofen, an agonist of the GABAB
receptor, injected into the PVN, on
apomorphine-, oxytocin- and NMDA-induced penile
erection and yawning. [...]
As found in previous studies, apomorphine
(50 ng), oxytocin (10 ng) or NMDA (50 ng)
injected into the PVN induced repeated penile
erection and yawning episodes when compared to
vehicle (saline. Muscimol (50-200 ng) reduced
dose-depenilently penile erection and yawning
induced by apomorphine, oxytocin or NMDA when
injected into the PVN 10 min before the above
compounds. Muscimol effect on
NMDA-induced penile erection and yawning was
seen already at the dose of 50 ng, which reduced
NMDA responses by more than 50%, while a dose of
100 ng was required to reduce oxytocin and
apomorphine responses by the same extent. The
maximal effect on NMDA responses was found with
100 ng, while 200 ng were necessary to reduce
apomorphine and oxytocin responses almost
completely. In contrast, baclofen (200
ng) was unable to reduce penile erection and
yawning induced by apomorphine, oxytocin and
NMDA when injected into the PVN 10 min before
these compounds. At the doses injected into the
PVN, muscimol and baclofen did not induce penile
erection, yawning or any visible gross
behavioral change or motor disturbances (not
shown).
Fig. 2 shows that bicuculline (250 ng)
prevents the reduction by muscimol of penile
erection and yawning induced by apomorphine,
oxytocin and NMDA, when injected into the PVN 5
min before muscimol (100 ng). At the dose
injected into the PVN, bicuculline did not
induce penile erection, yawning or any gross
behavioral change (not shown).
The present results show that muscimol, a
GABAA receptor agonist, but not baclofen, a
GABAB receptor agonist, given into the PVN
reduces penile erection and yawning induced
by apomorphine, oxytocin or NMDA. Since
baclofen, which is several times more active
than muscimol on GABAB receptors, is unable to
prevent these responses, and muscimol effect is
abolished by bicuculline, a GABAA receptor
antagonist, muscimol apparently reduces penile
erection and yawning induced by the above
compounds by stimulating GABAA receptors in the
PVN.
It is likely that these GABAA receptors
are located in the cell bodies of
paraventricular oxytocinergic neurons projecting
to extrahypothalamic brain areas, which mediate
these behavioral responses (see above). As
GABAergic synapses impinge on parvocellular and
magnocellular oxytocinergic neurons, the finding
suggests that GABAergic synapses also impinge on
and control in an inhibitory fashion
oxytocinergic neurons mediating penile erection
and yawning.
Surprisingly, muscimol reduced penile
erection and yawning induced by NMDA at doses
lower than those required to reduce the above
responses induced. by oxytocin and apomorphine.
This indicates that the activation of
oxytocinergic neurons mediating penile erection
and yawning by NMDA is more sensitive to
GABAergic inhibition than the activation by
apomorphine or oxytocin. One possibility is that
muscimol acts not only on GABAA receptors
located in the cell bodies of oxytocinergic
neurons to inhibit their activation by NMDA,
apomorphine or oxytocin, but also on GABAergic
receptors that control an endogenos excitatory,
possibly glutamatergic input to
oxytocinergic neurons.
This would cause, in turn, a decrease in the
release of endogenous glutamic acid, thereby
producing a more pronounced inhibition of
oxytocinergic neurons, which makes them less
sensitive to the injected exogenous NMDA. In
line with this hypothesis excitatory
glutamatergic synapses impinge on
paraventricular oxytocinergic neurons.
Alternatively, the higher doses of muscimol
required to reduce apomorphine and oxytocin
responses, when compared to NMDA responses,
might simply reflect the different molecular
mechanisms mediating apomorphine- oxytocin- and
NMDA-induced penile erection and yawning.
Namely, although a Ca 2+ influx apparently
mediates NMDA-, apomorphine and oxytocin-induced
penile erection and yawning, NMDA induces these
responses by acting on NMDA receptor-coupled
voltagedepenilent Ca 2+ channels, while
apomorphine and oxytocin activate
(½-conotoxin-GVIA-sensitive Ca 2+ channels.
Whatever mechanism may be responsible for the
different sensitivity to muscimol of NMDA,
oxytocin and apomorphine responses, muscimol
prevents penile erection and yawning induced by
all the above compounds, suggesting that GABA
exerts an inhibitory control on oxytocinergic
neurons mediating these responses as found with
other oxytocinergic neurons. Accordingly, GABA
inhibits oxytocin release induced by suckling
and by osmotic stimuli. Whether the ability of
muscimol to reduce penile erection and yawning
reflects a physiological role of GABAA receptors
at the PVN level in these behavioral responses
cannot be decided from the present results.
Indeed, in our experimental conditions control
rats show very low values of penile erection and
yawning, making it impossible to detect an
inhibitory effect of muscimol on spontaneous
penile erection and yawning in these animals.
However, as bicuculline, which blocks GABAA
receptors, is unable per se to induce penile
erection and yawning when injected into the PVN,
paraventricular GABAergic synapses that control
oxytocinergic neurons mediating these behavioral
responses are apparently not tonically
active.
Although GABA is the major inhibitory
neurotransmitter in the brain, its role in the
control of penile erection and yawning is poorly
understood. In agreement with our results, it
has been recently reported that muscimol given
systemically reduces penile erection induced by
apomorphine [20], and that GABA agonists
reduce penile reflexes induced in restrained
male rats after retraction of the penile sheath
[5] and impair copulation [5,9,141.
However, in contrast with the present results,
these studies also reported that baclofen given
systemically reduces'penile erection induced by
apomorphine [201 and penile reflexes in
restrained male rats, apparently by acting in
the lumbosacral spinal cord. Baclofen was also
found able to reduce yawning in two sublines of
rats showing high and low spontaneous yawning
frequency. This discrepancy may be due to
several reasons. Firstly, the majority of
studies quoted above, like many other studies in
which GABAergic drugs are given systemically,
are complicated by the often dramatic sedative
effects of these compounds. This causes severe
motor disturbances that interfere with many
behaviors, making it impossible to clarify a
specific role of GABA in the responses studied.
Secondly, GABAergic drugs given systemically
reach all brain structures, and the observed
effect is the algebraic sum of the actions
induced by these compounds at all reached sites.
In particular, GABAergic stimulation of GABAA
and GABAB receptor might produce different, e.g.
inhibitory or excitatory, effects on yawning and
penile erection, depending on the brain area in
which they act. Although further studies are
necessary to clarify the mechanism(s) by means
of which GABA receptor agonists influence penile
erection and yawning, this study shows for the
first time that GABAA receptors are involved in
the qontrol of penile erection and yawning at
the PVN level.
Melis MR ,
A.Argiolas. Reduction of drug-induced
yawning and penile erection and of noncontact
erections in male rats by the activation of
GABAA receptors in the paraventricular nucleus:
involvement of nitric oxide Eur J Neurosci
15(5): 852-60.(2002)
Melis MR, Spano
MS, Succu S, Argiolas A Activation of
gamma-aminobutyric acid(A) receptors in the
paraventricular nucleus of the hypothalamus
reduces apomorphine-, N-methyl-D-aspartic acid-
and oxytocin-induced penile erection and yawning
in male rats. Neurosci Lett 2000 Mar
10;281(2-3):127-30
Zarrindast
MR, Toloui V, Hashemi B Effects of GABAergic
drugs on physostigmine-induced yawning in rats;
Psychopharmacology (Berl) 1995
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