Septohippocampal
cholinergic pathway and penile erections induced
by dopaminergic and cholinergic
stimulants
Noriaki Maeda, Nobuya Matsuoka and Isamu
Yamaguchi
Basic Research Group,
Tsukuba Research Laboratories, Ibaraki
(Japan)
It has been reported that the direct and
indirect dopaminergic stimulants, apomorphine
and amantadine, induce- penile erections in male
rats. Penile erection was attenuated by both
dopaminergic and cholinergic antagonists,
suggesting that dopaminergic stimulation causes
cholinergic activation.
There have been papers on studies of the
sites of the interaction. An involvement of the
septum and striatum has been indicated from a
study on apomorphine-induced yawnings
which occur simultaneously with penile
erections. In contrast, Melis et al. proposed
that the
paraventricular nucleus of the hypothalamus
(PVN) is the area of the brain where
dopamine agonists act to induce penile erection
and yawning.
Electrophysiological studies, however,
suggest that the hippocampus has a crucial role
in expressing penile erections. This brain area
is sparsely innervated by dopaminergic nerves,
while densely innervated by cholinergic nerve
fibers derived from cells in the medial septum.
Furthermore, the cells in the septum receive
inhibitory influences from the A10 dopaminergic
cell bodies.
In the present paper, we studied the effects
of septohippocampal denervation on penile
erections induced by dopaminergic and
cholinergic stimulants. The denervations were
achieved either by medial septum or
fimbria-fornix lesions. [...]
DISCUSSION
It is a novel finding that penile erections
are elicited in rats by systemic administration
of pilocarpine. The pilocarpine-induced penile
erections were attenuated by scopolamine but not
by methylscopolamine. These results suggest that
an activation of central muscarinic receptors is
responsible for the penile erection. However,
Gower et
al. reported that physostigmine did not
elicit penile erections. Differences in the
specificity of the action of pilocarpine and
physostigmine might explain this discrepancy.
Physostigmine inhibits cholinesterases, no doubt
stimulating nicotinic receptors as well as
muscarinic receptors. Furthermore, muscarinic
receptors are now divided into Ml, M2 and M3
subtypes. Pilocarpine is reported to be more
specific for muscarinic Ml receptors'. At low
doses of pilocarpine, penile erection may be
induced by preferential stimulation of Ml
subtype, whereas at higher doses, the score of
penile erection tended to decline, presumably
due to its general stimulation of these
subtypes. There seems to be a marked difference
in the frequency of basal penile erections in
the two studies. Control rats in the present
study showed considerable number of penile
erections (0.3-0.7 times/h), while those
observed by Gower et al. showed minimal
erections. Central cholinergic tone may be
depressed in the latter experiment. Our rats
were subjected to handling prior to use, which
could be responsible for the difference.
McLean, after a series of
electrophysiological studies, concluded that the
hippocampus and its afferents are important for
the expression of penile erections. The
hippocampus is densely innervated by,
cholinergic nerve fibers which originate from
the septum and course through the
fimbria-fornix. In the present study, medial
septum and fimbria-fornix lesions decreased
hippocampal ChAT activity by 45.2 and 93.7%,
respectively, and abolished amantadine- and
apomorphine- but not pilocarpine-induced penile
erections. Furthermore, scopolamine but not
methylscopolamine suppressed the penile
erections induced by amantadine and apomorphine
in agreement with previous papers. It is thus
speculated that intact cholinergic nerve
activities are necessary for amantadine and
apomorphine to induce penile erections. In
contrast with these dopaminergic stimulants,
pilocarpine may directly stimulate muscarnic
receptors.
Sulpiride, a dopamine antagonist, attenuated
penile erections induced by amantadine and
apomorphine, but hardly affected those by
pilocarpine. At first sight, these results, when
combined with those mentioned above, would seem
to suggest that the cholinergic and dopaminergic
influences on penile erection might be mediated,
respectively, through the septohippocampal
cholinergic pathway and the dopaminergic
innervation of the cholinergic cells of origin
of that path. However, the septohippocampal
cholinergic nerves receive an inhibitory
influence from the dopaminergic cells of the A10
region , and dopaminergic antagonists such as
halperidol or lesioning with 6-hydroxydopamine
have been shown to increase acetylcholine
turnover rate in the hippocampus. There is a
belief that apomorphine activates postsynaptic
dopamine receptors at higher doses, hence, if
the dopaminergic drugs used here were acting at
postsynaptic receptors in the septum, agonists
should be expected to decrease penile erection
and antagonists to increase it. The opposite was
found to be the case. One might argue in the
case of apomorphine that the low doses found
effective in stimulating penile erection were
acting preferentially at presynaptic
autoreceptors in the septal region to reduce
inhibition of the cholinergic neurons. However,
this would not explain the very similar findings
with amantadine which has been reported to
indirectly stimulate the dopaminergic nerves and
has not shown to have any such presynaptic
action. The autoreceptor hypothesis has recently
been questioned by many authors.
The alternative, therefore, is to consider
that the primary action of the dopaminergic
drugs with regard to penile erection is in some
other brain region, with the effects being
expressed through other, non-dopaminergic
influences on the septohippocampal tract. In
this respect, it is interesting to note the
hypothesis proposed by Argiolas
et al. that apomorphine interacts with
postsynaptic dopamine receptors in the PVN of
the hypothalamus to stimulate the activity of
oxytocinergic neurons, which in turn mediate the
appearance of penile erection. a Melanocyte
stimulating hormone and adrenocorticotropic
hormone both induce penile erections, and their
activities are well correlated with the increase
of acetylcholine turnover in the hippocampus.
Such an activity might be shared with
oxytocin.
Recently, several subtypes of dopamine
receptors have been postulate. As apomorphine is
known to act as a mixed D1-D2 agonist, it is
probable that we see the combined effects
mediated by these subtypes when apomorphine is
administered systemically. Bitran et al. have
shown that microinjection of quinelorane, a D2
agonist, into the medial preoptic area inhibited
penile erection while apomorphine facilitated
it. Activation of various subtypes of
postsynaptic receptors in the
incertohypothalamic dopaminergic system might
occur at different concentrations of agonist and
contribute to the bell-shaped dose-response
curves. These possibilities remain to be
elucidated.
