Dopaminergic
stimulation of oxytocin concentrations in the
plasma of male and female monkeys by apomorphine
and a D2 receptor agonist
JL Cameron, SM Pomerantz, LM Layden, JA
Amico
Departments of Behavioral
Neuroscience Medicine, Physiology,and
Psychiatry, University of Pittsburgh School of
Medicine, and Oakland Department of Veterans
Affairs Pittsburgh, Pennsylvania
0xytocin is a nonapeptide that is
synthesized in magnocellular and parvocellular
neurons of the paraventricular and supraoptic
nuclei of the hypothalamus and is released from
the mammalian neurohypophysis in response to
appropriate physiological stimuli. The release
of oxytocin into the peripheral circulation has
been associated with a variety of
reproductive-related behaviors, including milk
ejection, labor and delivery, ovulation, and
coitus. Moreover, the administration of oxytocin
into the central nervous system of rodents
elicits specific reproductive-re- lated
behaviors, such as the induction of maternal
behavior and sexual behavior in male and female
rats.
Peripheral administration of the dopamine
receptor agonist apomorphine, which binds to
dopamine D1 and D2 receptors, causes penile
erection and yawning in male rats in
conjunction with increases in plasma oxytocin
con- centrations. Moreover,
intracerebroventricular (icv) in jection of
oxytocin into rats elicits penile erection and
yawning in male rats. Penile erection and
yawning induced by administration of
either icv oxytocin or peripheral apomorphine
are antagonized in a dose-dependent manner by
icv pretreatment with an oxytocin antagonist.
These observations suggest that dopamine
facilitates oxytocin release in male rats and
that oxytocin may mediate these behaviors in
rodents.
Although little is known regarding the roles
of oxytocin and dopamine in sexual behavior in
primates, recent studies have demonstrated that,
similar to rats, apomorphine facilitates male
sexual behavior in rhesus monkeys and penile
erections in normal and impotent men. Whether
these behavioral effects of apomorphine in
primates are mediated through oxytocin release
is unknown. Therefore, in the present study we
administered dopamine receptor agonists to male
and female monkeys and monitored both the
oxytocin secretory responses in peripheral blood
and behavior in order to correlate
neuroendocrine and behavioral responses to these
agents.
[...]
Discussion The results of this study
in monkeys are in partial agreement with those
of previous studies performed in rats. We found
that the dopaminergic receptor agonist
apomorphine increased the concentration of
oxytocin in the peripheral circulation of
monkeys, as it did in rodents, in a
dose-dependent fashion.
In rats, no significant oxytocin secretory
response was seen with an apomorphine dose of 80
µg/kg. In monkeys, increases in oxytocin
were not found at low doses (e.g. 50
µg/kg), but were elicited as the dose was
increased. The oxytocin secretory response to
apomorphine was observed in female rhesus
monkeys as well as in male rhesus and cynomolgus
monkeys, indicating that the response is not sex
related or species specific.
The oxytocin secretory response was quite
variable among the animals, with some monkeys
displaying marked increases, and others
displaying minimal increases in plasma oxytocin
concentrations. The cause of the variable
oxytocin response to apomorphine among the
different animals used in this study is not
known. However, a similar variability in
behavioral responses to apomorphine was found
(as discussed below). Interestingly, within
given monkeys there was a strong correlation
between the oxytocin and behavioral responses to
apomorphine, so that monkeys who showed the
most dramatic oxytocin secretory responses to
the high doses of apomorphine (e.g. 200 and 400
pg/kg) also showed the greatest amount of
stereotypic behavior and hypermobility at these
doses. This finding suggests that these
responses to dopamine stimulation may be linked
to each other and that a threshold for
responsiveness may exist that is variable among
animals. Alternatively, the oxytocin and
behavioral responses to apomorphine may be
unrelated to each other, and the variable
responses among animals may result from
differences in factors such as dopamine receptor
distribution or availability.
Since the effects of apomorphine on the
release of neurohypophysial hormones in rodents
are believed to be mediated by the dopamine D2
receptor, we administered dopamine D1 and D2
receptor agonists to the monkeys to evaluate
whether one or both of these dopamine receptor
subtypes were responsible for regulating
oxytocin activity. A dose-related release of
oxytocin was found with the dopamine D2 receptor
agonist LY 163502, whereas only a nonsignificant
increased trend in plasma oxytocin
concentrations was found with the highest dose
(400 µg/kg) of CY 208-243. This trend
toward an increase in oxytocin concentrations by
the dopamine D1 receptor agonist CY 208-243 at a
dose of 400 µg/kg, but not at lower doses,
may be explained by the moderate affinity of
this particular agonist for dopamine D2
receptors. Importantly, CY 208-243 did not
elicit any behavioral effects in these animals,
whereas both apomorphine and the dopamine D2
receptor agonist LY 163502 elicited dose-related
stimulations of oxytocin coupled with
dose-specific behavioral changes in monkeys.
Thus, dopamine D2 receptors, as opposed to D1
receptors, may be primarily responsible for
regulating oxytocin secretion inprimates.
In rodents, there is abundant evidence that
apomorphine induces penile erection and
yawning by releasing oxytocin into the
central nervous system. In rodents low doses of
apomorphine (40 and 80µg/kg) elicit
yawning and penile erections, whereas
doses of apomorphine of 100µg/kg or more
cause hypermobility and stereotypy. In monkeys,
although low doses of apomorphine (5O-100
µg/kg) elicited yawning in the male
and female monkeys that were studied and penile
erections in two of the four male monkeys
administered 100 wg/kg apomorphine, only a
modest increase in oxytocin secretion was
observed. In contrast, whereas yawning
and penile erections were rarely observed at 100
µg/kg apomorphine, these doses produced a
substantial release of oxytocin as well as oral
dyskinesia and stereotypy in all monkeys that we
studied. Thus, it seems unlikely that in
macaques, oxytocin mediates the behaviors of
yawning and penile erections that are
elicited by apomorphine administration. Of
course, however, final proof of this conclusion
will only be determined in experiments examining
the behavioral responses to apomorphine in the
presence of an oxytocin antagonist or
antiserum.
To the best of our knowledge, dopamine's
influence on plasma oxytocin concentrations has
not been previously tested in monkeys.
Apomorphine has been reported to increase the
circulating concentrations of the closely
related neurohypophysial peptide arginine
vasopressin (AVP) in humans. The stimulus for
apomorphine release of AVP in humans was found
to be independent of volume or osmolar stimuli
and thought to be mediated by the induction of
nausea, because pretreatment of humans with an
antiemetic agent typically abolishes the
apomorphine-induced release of AVP. The doses of
apomorphine used to induce nausea in humans
ranged from 5-50 µg/kg BW and have produced
a brisk AVP release without an associated
release of oxytocin or with minimal but
statistically significant increases in plasma
oxytocin. In addition, prior reports by Verbalis
and co-workers have indicated that other
nauseogenic agents, such as lithium chloride,
copper sulfate, or cholecystokinin, selectively
increase AVP, but not oxytocin, concentrations
in nonhuman primates.
Based upon these observations, Verbalis and
co-workers have suggested that there is a
specific neurohypophysial hormone secretion in
response to nauseogenic agents involving the
release of AVP, but not oxytocin, in primates.
In contrast to the studies with humans, our
findings indicate that high doses of apomorphine
(>50 pg/kg) can elicit both AVP and oxytocin
release in primates, as shown by our recent
finding that the same high doses of apomorphine
(e.g. 50-400 µg/kg) used in the present
study also elicit AVP release in monkeys.
Oxytocin release in monkeys with high doses of
apomorphine may or may not be induced bynausea.
Surprisingly, the doses of apomorphine used in
the present study did not elicit emetic behavior
in any of the monkeys, although these were
higher doses of apomorphine than those that
induced nausea and emesis in humans.
However, although no monkeys in this study
displayed emetic behavior, we have no way of
knowing if they were feeling nauseated. It is
also possible that apomorphine is less of a
nauseogenic agent in monkeys than in humans and
that the responses of oxytocin and AVP to
apomorphine that we found in monkeys are
independent of nausea. Further studies in which
monkeys are pretreated with an antiemetic agent
could potentially help resolve this issue.
An important finding from this study is that
dopamine receptor agonists release oxytocin into
the plasma of primates. Few stimuli are known to
release oxytocin into primate plasma. Of these,
suckling is the most reproducible physiological
stimulus for oxytocin release. However, no
pharmacological stimulus for oxytocin release
has previously been identified in primates,
although a few pharmacological agents are known
to release oxytocin in rodents (i.e. chole-
cystokinin and apomorphine). The lack of a
pharmacological stimulus to elicit oxytocin
secretion in primates has made study of this
peptide in primate species difficult.
By identifying dopaminergic agonists, and in
particular D2 receptor agonists, as potent
inducers of oxytocin release in monkeys, these
agonists may become useful pharmacological tools
for further studies exploring the physiological
actions of oxytocin in primates as well as for
studies examining the pharmacological systems
influencing oxytocinergic neurons in
primates.
