Department of Urology,
Faculty of Medicine Queen's University,
Kingston, Ontario
Abstract:
Acute administration of metoclopramide, a
dopamine (D2) antagonist, reduced both
apomorphine-induced yawning and penile
erections. Metoclopramide, prominent in clinical
use as an effective antiemetic, has been shown
to be associated with decreased erectile
function in humans. Experimentally naive rats
were given a standardized dose of apomorphine
and one of a range of doses of metoclopramide.
The study shows that metoclopramide decreases
the erectile response to apomorphine and
suggests that the erectile difficulties
experienced in humans after metoclopramide
treatment may be a result of interference with a
central dopaminergic mechanism(s).
APOMORPHINE (APO) is a dopamine
receptor agonist that has been shown to produce
a syndrome of yawning and penile erection in
rats. The increase in both yawning and erection
seen after APO administration is in direct
contrast to the low spontaneous rates of these
behaviors seen after administration of saline.
This phenomenon has been harnessed to form an
effective bioassay for the testing of the
erectolytic (erection-diminishing) effects of
various pharmaceutical agents.
The specific mechanisms by which APO acts to
produce an erectile response are not yet
completely understood, however, several
hypotheses have been put forth on the basis of
the properties of the response to explain the
phenomenon. APO has been documented to have a
biphasic effect on yawning behavior. Yawning
behavior is initiated at approximately 20-25
µg/kg and is inhibited by doses exceeding
400-500 µg/kg. It has been shown that a
decrease in yawning frequency at higher doses of
APO parallels the decrease in the number of
erections. It has been postulated that low doses
of APO cause yawning by preferential stimulation
of dopaminergic presynaptic receptors or
autoreceptors, while higher doses have been
shown to exert a stimulatory effect on
postsynaptic neurons. This view, however, has
been challenged recently by Stahle and
Ungerstedt. They showed that, if basal levels of
DA are increased by approximately 200% by the
administration of amphetamine, it is still
possible to induce yawning behavior using low
doses of APO. Yet, according to the autoreceptor
hypothesis, it is a reduction in basal levels of
DA via autoreceptor stimulation that is
responsible for PE/SYS.
Other studies are also felt to provide
evidence counter to the autoreceptor hypothesis.
These studies provide evidence that high doses
of APO elicit an erectile/yawning response and
are thus felt by some to be counter to the
hypothesis explaining the behavior through the
action of low doses activating dopaminergic
autoreceptors. Although the ability of high
doses of APO to stimulate an erectile response
could probably be taken as evidence against the
autoreceptor hypothesis a fundamental aspect
becomes evident when reviewing these studies.
For example, a study where the erectile response
is stimulated by high doses of APO given by oral
intubation cannot be compared, in terms of
dosing, with those studies using APO
administered by the subcutaneous or
intraperitoneal route as APO has been shown to
have very poor oral bioavailability. Again, the
study by Hull et al. used the direct infusion of
high doses of APO to study the effects on sexual
behavior. High doses of APO administered to the
lateral ventricle or medial preoptic area
increased sexual behavior as defined by an
increased ejaculation frequency or a decreased
intermission interval. However, can this be
taken as evidence against the autoreceptor
hypothesis? With high doses of directly infused
APO the risk of spreading of drug into adjacent
areas that are more directly involved in the
PE/SYS phenomenon, but require low doses, must
be considered. In fact, it has been shown that
low doses of APO infused into the
paraventricular nucleus (PVN) are effective in
stimulating a yawning and erectile response,
while lesioning of this nucleus abolished the
ability of systemic APO to induce the response.
Thus high doses of APO infused in areas in close
proximity to the PVN may indeed elicit a
response. In light of the above, caution must be
exercised when evaluating studies that examine
APO and its ability to produce PE/SYS or
confusion may be added to the already
complicated picture of the mechanism of this
response.
Although the specific mechanism of
APO-induced PE/SYS remains unidentified, most
investigators agree that the response is the
result of central stimulation rather than the
direct peripheral stimulation of the penile
vasculature (causing erection) or facial
vasculature (to cause yawning). Sulpiride and
haloperidol, central dopamine receptor blockers,
antagonize the ability of apomorphine to elicit
PE/SYS. The dopamine (D2) antagonist
domperidone, which unlike sulpiride and
halopendol is a peripherally acting agent, has
been shown to have no effect on APO-induced
penile erections. Thus yawning and probably the
accompanying erectile behavior, is felt to be
centrally mediated.
Regardless of the specific mechanism of
APO-induced PE/ SYS the establishment of a rat
bioassay for erectile function allows for the
testing of various pharmaceutical agents with
properties known or thought to have an impact on
the erectile pathway(s). Metoclopramide (MET) is
such an agent. The antagonistic actions of
metoclopramide are said to be four to five times
greater on the presynaptic receptors than on the
corresponding postsynaptic receptors. The
ability of MET to inhibit APO-induced yawning in
rats has suggested the present study that
examines the effect of MET on APO-induced
erections. These pathways and responses may play
an important physiological role in the central
control of some erectile responses and in some
erectile dysfunction.
DISCUSSION
The results of the present study show that
one known stimulant of erections in the rat,
apomorphine, may be antagonized by
metoclopramide a D2 blocker. The decrease in the
erectile response is paralleled by a decrease in
yawning behavior. This probably indicates that
the suppression of APO-induced erectile activity
is a result of central antagonism as is the
suppression of the yawning. It is not yet known
whether MET interferes with the normal sexual
response of the rat or whether MET interferes
with rocturnal erectile responses in the rat, if
indeed these responses are different.
In humans, MET is an effective antiemetic
with selective affinity for D2 receptors. MET
has been reported to be associated with
impotence. The mechanism by which MET reduces
erectile potential in man is unknown, although
the data presented here may point to an
alteration in dopaminergic mechanisms. However,
the bioassay of potency such as is described
here, may be used to examine the specific
mechanisms of these alterations in an animal
model in detail.
We have discussed one possible mechanism for
the interference of MET with APO-induced
erections and yawning, one that lies at the
level of D2 receptor blockade. There are other
potential sources of interaction. For instance,
MET has been shown to interfere with both
androgen and prolactin homeostasis. We have
recently shown that manipulation of the androgen
milieu degrades the erectile function of the
rat. Similarly, elevated serum prolactin is
associated with erectile dysfunction in animals
and man.
The validity of extrapolating the results of
the rat bioassay for potency and erectile
function to man is suggested by the reports that
man responds to APO with erection and it is not
unreasonable to speculate that MET may cause
erectile dysfunction in man by a similar
mechanism as that seen in the rat.
In summary, the above data illustrates how
the erectolytic effects of a drug may be modeled
and tested using APO induced erections as a
standard. The APO bioassay may be applied to
assess the impact of any physical or
pharmacological manipulation with a possible
effect on erectile function.
-Heaton JP,
Varrin SJ Effects of streptozotocin-induced
diabetes on dopaminergic functioning in the rat:
analysis of yawning behavior. Pharmacol Biochem
Behav. 1993; 44; 3; 601-604
