Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al
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1 mai 2003
J Clin Endocrinol Metabol
1992; 75; 3; 855-860
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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.
 dopamine D3
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.