- Summary
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- Quinelorane, a highly selective 02 dopamine
agonist, was assessed for its ability to induce
the penile erection/stretch-yawn syndrome.
Quinelorane (0.1 - 100 kg/kg s.c.) or saline
vehicle was administered to adult male
Sprague-Dawley rats just prior to a 30 min.
observation period. Significant dose-related
increases in erections were observed in the drug
treated animals at 3-100 jig/kg. Yawning was
also increased at 3-100 jig/kg, with highest
levels occurring at 10 jig/kg. Defecation was
stimulated between 10 and 100 jig/kg. The
stimulatory effects of 30 jig/kg of quinelorane
on erection, yawning and defecation were blocked
by haloperidol (0.1-0.3 mg/kg) but not by
domperidone (0.11.0 mg/kg). No significant
effects of quinelorane on seminal emission were
observed. These findings indicate that in
addition to its stimulatory effects on sexual
activity, quinelorane also acts on 02 receptors
in the central nervous system to stimulate
erection in the penile erection/stretch-yawn
model.
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- Quinelorane is a highly selective 02
dopamine (DA) agonist (15) that has been shown
to stimulate sexual activity in male and female
rats (12, 13). In males, quinelorane reduces
intromission and ejaculation latencies as well
as the number of intromissions required for
ejaculation. These effects are mediated by
interactions with 02 receptors within the
central nervous system (CNS; 12). The effects of
DA and DA agonists on sexual activity have often
been attributed to changes in motivation/reward
(1,4,23,26). However, DA receptor agonists also
influence erectile function. For example, the
mixed D1/D2 agonist, apomorphine, increases the
number of erections observed in the restrained
supine rat (ex copula penile reflex tests).
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- In addition, apomorphine affects several
aspects of copulatory behavior in the male rat
that have been associated with erectile
capacity, including intromission rate, the
percentage of mounts with intromission, and
ejaculation latency. These effects are observed
after subcutaneous injection,
intracerebroventricular administration, or by
direct infusion into the medial preoptic area
(MPOA; 18,24) Administration of apomorphine also
increases the occurrence of spontaneous
erections in rats (16), rhesus monkeys (27) and
men (7,20,33). Unlike apomorphine, quinelorane
inhibits erection and stimulates seminal
emission in rat penile reflex tests after
subcutaneous administration (5) or direct
infusion into the MPOA (2).
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- However, a moderate dose of quinelorane has
been shown to reduce reflex latency and increase
the number of intense erections and penile
movements during such tests in rats when
administered into the paraventricular nucleus of
the hypothalamus (PVN; 10). In addition,
quinelorane increases the display of erections
in rhesus monkeys after intra-muscular
administration and does so by stimulating
central DA receptors (28). The purpose of the
present experiments was threefold. First, we
wished to determine if quinelorane would induce
erection in the penile erection/stretch-yawn
syndrome (PE/SYS), a behavioral response that
may more closely parallel the effects of DA
agonists on erection in rhesus monkeys and men.
Second, we wanted to assess the participation of
D2 receptors in the CNS in this response.
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- Finally, since quinelorane administration
has been associated with seminal emission in
penile reflex tests (2,5), and since the
suggestion has been made that erection in PE/SYS
is occurring as a reflexive response to drug
induced emission (6), we have also examined the
degree to which penile erection can be
associated with seminal emission in PE/SYS after
quinelorane administration.
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- Discussion
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- The results of the present experiments
demonstrate that quinelorane can increase the
occurrence of spontaneous erections in the male
rat. This effect occurred within the dose range
that is stimulatory to sexual activity (12)
suggesting that the activation of penile
erection may contribute to the effects of
quinelorane on male sexual behavior. The
blockade of the erectile response by the
centrally acting antagonist, haloperidol, but
not by domp.eridone in doses that do not alter
CNS function in the rat (11), demonstrates that
the effects of quinelorane on erections occur
through stimulation of specific D2 receptors
located within the CNS. In this paradigm as well
as in tests of sexual activity, quinelorane is
apparently more potent than other dopamine
agonists including quinpirole, apomorphine, and
pergolide (12,16).
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- However, the threshold dose for stimulation
of the erectile response was higher than the
doses needed to induce significant changes in
tests of copulatory behavior (12). This shift in
threshold corresponds with differences in the
doses which restore mounting behavior versus
those that restore ejaculations in adult
non-maters (12). These results suggest that
higher doses of quinelorane may be required to
induce the erectile response than those needed
to increase sexual drive. However, we cannot
exclude the possibility that during standard
tests of copulatory behavior, exposure of a
sexually experienced male to an estrous female
may shift the sensitivity of the quinelorane
response. The presence of a female does enhance
the display of erections after quinelorane
treatment in rhesus monkeys (28).
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- Quinelorane and apomorphine induce similar
responses in PE/SYS (16), but strikingly
different effects in penile reflex tests (2,4,1
0,24,25). Their similarity of action in PE/SYS
appears to be due to stimulation of 02 receptors
(15,16). In contrast, much of the difference in
the activity of these two drugs on ex copula
penile reflexes may involve the low affinity of
quinelorane for the D receptor (15). It has
recently been proposed that the brain exerts a
dual influence on spinal centers involved in
erection; disinhibition and excitation (30).
According to this scheme, reduced erection
latencies in penile reflex tests reflect
disinhibition while increased numbers of
erections represent excitation. Bazzett et al.,
have proposed that 02 and D1 receptor
stimulation in the MPOA may correlate with
disinhibition and excitation, respectively, of
erections in penile reflex tests. Thus,
apomorphine by stimulating both D1 and D2
receptors can decrease erection latency
(disinhibition) and increase erections
(excitation).
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- Quinelorane, on the other hand, through
selective stimulation of D2 receptors, decreases
erection latency (2,19). It apparently does so
both in tests of penile reflexes and in PE/SYS.
The latter conclusion is limited, however, by
the fact that a major effect of quinelorane on
erection in PE/SYS is to increase the proportion
of animals displaying erections during a set
time period. The increase in the number of
erections that is also observed may be mediated
by stimulation of 02 receptors at sites other
than the MPOA, such as the PVN (22). Infusion of
both apomorphine (25) and quinelorane (10) into
the PVN decreases erection latency and
stimulates erections and emission in penile
reflex testing.
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- The suggestion that seminal emission plays a
role in the erections observed in PE/SYS has
arisen from several lines of evidence. First,
quinelorane increases seminal emission and
decreases the number of erections in penile
reflex tests (2,5). It also decreases
ejaculatory thresholds in tests of copulatory
behavior (5,12). Furthermore, the display of
erections in penile reflex tests is inhibited
after the occurrence of emission, a phenomenon
that has been likened to the post-ejaculatory
refractory period. In addition, dopamine agonist
induced erections in PE/SYS occur with a
frequency that parallels the number of
ejaculations in tests of copulatory behavior
rather than the number of intromissions
preceding ejaculation. It has seemed logical,
therefore, to assume that erections observed in
PE/SYS might be occurring as a reflexive
response to emission (6,31), similar to the
induction of coital reflexes after stimulation
of the urethral bulb with saline (21), rather
than a direct stimulation of erection.
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- The experiment presented herein represents
the first time that the occurrence of seminal
emission during PE/SYS has been examined in a
systematic fashion. It has been our experience,
using not only quinelorane but also a variety of
other dopamine agonists, that emissions occur
infrequently (Doherty and Wisler, unpublished
observations), and more often than not, the
animal neither grooms in response to the
emission nor does it display an erection. The
lack of significant coincidence of erection with
emission in the present experiment indicates
that it is unlikely that emission is either a
cause of, or a necessary requirement for
erection in PE/SYS.
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- PE/SYS has been widely used as a drug screen
(3,16). Examination of its relationship to the
effects of hormones and neurotransmitters on
sexual activity has occurred only recently
(17,31). The demonstration that this response is
androgen dependent (17), but that acute
treatment with dihydrotestosterone propionate
does not restore the response (3), as can be
shown for erections in penile reflex testing
(31), demonstrates that hormones influence each
of these models of the erectile response through
interactions with different areas of the CNS.
There appears to be a high degree of
correlation, however, between the ability of
dopamine agonists to induce erections in PE/SYS
with similar results that have been observed in
the rhesus monkey and in man (3,7,16,20,27,33).
It may also be relevant that emission has not
been reported in association with dopamine
agonist induced erections in either rhesus
monkeys or men. Thus, this behavioral model
appears to be a useful paradigm for the
development of tools in the diagnosis and
treatment of erectile dysfunction (14,17).
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- The ability of dopamine agonists to increase
defecation in the rat has not been widely
reported. Since domperidone failed to alter the
effects of quinelorane on defecation, the
results of the present study demonstrate that
this response is mediated by DA receptors within
the CNS. The stimulatory effects of quinelorane
on defecation commence with doses that induce
peak numbers of erections but at which yawning
is rapidly decreasing. Thus, the defecation
response may be mediated by DA receptors at
different sites from those at which yawning and
penile erection are induced. Potential sites of
action include neurons in the MPONanterior
hypothalamic region that influence marking
behaviors like urination and defecation (9), or
nigro-striatal DA neurons. Defecation has
recently been correlated with changes in the
levels of dopamine and its metabolites in the
corpus striatum (29).
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- In summary, the results of the present study
show that quinelorane increases the occurrence
of spontaneous erections in the male rat through
a direct interaction with D2 receptors in the
CNS. Moreover, the erectile response observed
appears to be unrelated to any effects of
quinelorane on seminal emission. However, this
response may be related to both the increased
copulatory efficiency and decreased ejaculatory
threshold that have been seen previously with
this compound in tests of male sexual activity
(12). Though we are unable, on the basis of the
results of this study, to precisely localize CNS
structures involved in this response, one
potential site may be the PVN. Implantation of
quinelorane into this nucleus has been reported
to increase the number of intense erections and
penile movements in penile reflex tests
(10).
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