mise à jour du
21 décembre 2010
Life Sciences

 Stimulatory effects of quinelorane on yawning
and penile erection in the rat 
Paul C. Doherty and Petra A. Wisler
Lilly Research Laboratories Indianapolis USA


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.
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).
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).
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.
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.
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).
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).
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).
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.
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.
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.
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).
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).
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).