The intracerebroventricular (ICV)
administration of adrenocorticotropin (ACTH) and
related peptides induces a peculiar
symptomatology characterized by recurrent
episodes of stretching, yawning, penile erection
and ejaculation in different experimental
animals.
In rats, the symptomatology begins 25-30 min
after the treatment and lasts for several hours.
The reason for the delay in the onset of the
effect and the mechanism by which ACTH acts in
the central nervous system to induce these
behavioral responses are unknown, although the
hypothalamus is believed to be the brain site
where the peptide acts to induce the above
effects and pharmacological studies suggest that
central cholinergic and opioid transmission are
involved.
As to the physiological significance of
these behavioral responses, while the importance
of penile erection in reproduction does not need
to be stressed, it is pertinent to recall that
stretching and yawning have been considered to
have the role of increasing attention when sleep
is pressing in front of a danger or social
circumstances. With the aim to clarify the
mechanism by which ACTH and related peptides
induce the above behavioral responses, we
studied the effect of calcium channel blockade
on ACM-induced stretching, yawning and penile
ereclion. Furthermore, since penile erection and
yawning can be also induced by the dopaminergic
agonist apomorphine and oxytocin, the
relationship among ACTH, dopamine and oxytocin
in the expression of these behavioral responses
was investigated.[...]
Discussion: The present results show
that ACTH-induced stretching, yawning and penile
erection are prevented in a dose-dependent
manner by w-conotoxin, a rather potent and
selective inhibitor of N-type calcium channels
present mainly in the nervous tissues, but not
by organic calcium channel inhibitors belonging
to different chemical classes such as
nimodipine, verapamil and flunarizine.
The finding suggests that ACTH induces the
above behavioral responses by mobilizing calcium
through N-type calcium channels in some neuronal
population in brain. The involvement of the
other types of calcium channels (i.e., L and T)
in the expression of ACTH effects seems to be
minor, being organic calcium channel inhibitors
unable to modify ACTH responses. In contrast,
the ability of both organic calcium channel
inhibitors and of w-conotoxin to inhibit
apomorphine- and oxytocin-induced yawning and
penile erection suggests that L- or T-type
calcium channels also other than those of the
N-type play an important role in these
behavioral responses induced by apomorphine and
oxytocin.
Together the above findings suggest that
ACTH induces yawning and penile erection by
acting with a mechanism different from that of
oxytocin and apomorphine. A similar conclusion
is also supported by the ability of PVN
w-conotoxin microinjections to prevent
apomorphine and oxytocin effect but not that of
ACTH.
This is in agreement with previous studies
showing that ACTH acts by a mechanism not
involving hypothalamic dopamine or oxytocin.
Accordingly, while the PVN is the most
sensitive brain area for the induction of penile
erection and yawning by oxytocin and
apomorphine, other hypothalamic brain areas are
involved in the expression of ACTH-induced
yawning, and ACTH-induced penile erection and
yawning are prevented neither by dopaminergic
antagonists nor by oxytocin antagonists nor by
electrolytic lesions of the PVN. Conversely,
apomorphine- and oxytocin-induced penile
erection and yawning are prevented by oxytocin
antagonists with a rank order that ows their
potency in blocking oxytocin receptors but not
by the depletion of hypothalamic ACTH-MSH-like
peptides induced by neonatal treatment with
monosodium glutamate, suggesting that, while
apomorphine induces the above responses by
releasing oxytocin in the central nervous
system, neither apomorphine nor oxytocin effect
are mediated by the release of an ACTH-like
peptide in brain.
Other than those recalled above, three other
important features distinguish ACTH-induced
symptomatology from that induced by apomorphine
or by oxytocin: the requirement of much higher
doses (2-3 nmol ICV of ACTH 1-24 versus 10-50
pmol ICV of oxytocin or 40-80 µg/kg SC of
apomorphine, respectively); a much longer delay
in the onset of the effect (25-30 min for ACTH
and 5-10 min for oxytocin and apomorphine,
respectively); and a more long-lasting effect
(several hours for ACTH and 45-60 min for
apomorphine and oxytocin, respectively).
Our data support a role for calcium
involvement in the expression of stretching,
yawning and penile erection induced by
ACTH-related peptides. As to the mechanism by
means of which ACTH induces calcium
mobilization, only some speculation is possible
at present. One possibility is that ACTH
directly activates calcium channels or
influences one of the various biochemical
systems known to modify calcium homeostasis,
such as phosphoinositide turnover, ATPase
activity or calcium binding to calmodulin-like
proteins. In this regard it is noteworthy that
ACTH and related peptides affect
phosphatydilinositol metabolism in membrane
fractions from rat brain, inhibit the activity
of a brain protein kinase and consequently the
calcium-dependent phosphorylation of its
substrate proteins, and increases intracellular
calcium concentration in target cells.
Other than those recalled above, ACTH and
related peptides induce also other neurochemical
and electrophysiological changes in the central
nervous system. Namely, they increase neuronal
firing, cyclic adenosine monophosphate (c-AMP)
formation and increase acetylcholine and
catecholamine transmission and acetylcholine
turnover as well. These changes might be also
involved in the expression of yawning,
stretching and penile erection, since our data
do not rule out the possibility that w-conotoxin
blocks calcium channels at sites located
downstream rather than upstream to these events.
In view of the existence of a central
opiomelanocorticotropinergic system originating
in the hypothalamus and projecting to several
extrahypothalamic brain areas, further studies
are necessary to clarify the site where ACTH and
related peptides act to induce these behavioral
responses and other central effects as well
In conclusion, although more experiments are
necessary to clarify the mechanism responsible
for calcium mobilization, and to identify the
site where this mobilization would occur, the
present results suggest that calcium might be
one of the second messenger which mediates
stretching, yawning and penile erection induced
by ACTH and related peptides.
