Sexual Incentive Motivation and Copulatory Behavior in Male Rats Treated with the Adrenergic α2-Adrenoceptor Agonists Tasipimidine and Fadolmidine: Implications for Treatment of Premature Ejaculation

Abstract

Background: Premature ejaculation is the most common sexual dysfunction in young men, and it often leads to reduced relationship satisfaction and quality of life.Aim: To determine the role of central and peripheral α2-adrenoceptors in the control of ejaculation and sexual incentive motivation in rats.Methods: Sexual incentive motivation was studied in a large arena in which a male subject could choose between approaching and remaining close to a sexually receptive female or another male.Sexual behavior was studied in standard observation cages in which a male was allowed to freely interact with a receptive female for 30 min. Two highly selective agonists at the α2-adrenoceptors, tasipimidine and fadolmidine, were administered before the tests. Low peripheral doses of fadolmidine has been reported to have effects mainly outside of the central nervous system, whereas at large doses also the central effects are evident. Outcomes:The time spent close to the receptive female in relation to the time spent with the male and measures of ambulatory activity were obtained from the test for sexual incentive motivation, while the habitual parameters of sexual behavior were recorded with the copulation test.Results: Tasipimidine prolonged ejaculation latency and the interintromission interval at the dose of 200 µg/kg when data from fast-ejaculating rats were used. No other sexual parameter was modified. A dose of 100 µg/kg was ineffective. There was no consistent effect on sexual incentive motivation, although modest sedation was observed. Fadolmidine, a drug that does not easily penetrate the blood-brain barrier, had no effect on sexual incentive motivation at any of the doses used (3, 30, and 100 µg/kg). The largest dose had clear sedative effects. The lower doses had no systematic effect on sexual behavior, not even when only fast or very fast ejaculating males were analyzed. Clinical Translation:The findings are relevant to the search for treatments for premature ejaculation that are specific enough to selectively delay ejaculation. Strengths & Limitations:The procedures used here are standard in the field and yield the most reliable data. Whether the effects observed in male rats are directly transferrable to men can only be determined through clinical studies. Conclusion:The observation that drugs acting at central but not peripheral α2-adrenoceptors prolong ejaculation latency without affecting any other parameter of sexual behavior or sexual incentive motivation suggests that this kind of drug may be suitable for treating premature ejaculation.

Evaluation of Serum Prolactin and Testosterone in Premature Ejaculation Patients

“…Elevation in serum prolactin in the primary PE patients (group I) was reported by Lehtimäki et al [32]. They reported an increase in serum prolactin among the primary PE patients than in the control group, but within the normal range, and speculated that, these higher prolactin levels might be the result, not the cause, of the loss of ejaculatory control in patients because of the presence of an elevated anxiety trait.…”

“…However, they did not define in their study the type of these hormonal disorders either increased or decreased. On the contrary, Lehtimäki et al [32], reported no significant difference in serum testosterone levels between primary PE patients and the control group.…”

“…In the present study, the same results can not be detected may be because of the serotonergic central changes, mirrored by low prolactin levels in both primary and secondary PE, that can be a consequence-and not a cause-of the absence of ejaculatory control. In fact, many psychological disturbances, such as stress and frustration for chronic or acquired inability to enjoy sex, are able to provoke a neuroendocrine imbalance, and this is proved by the therapeutic effectiveness of serotonergic antidepressants demonstrated in both primary and secondary PE [37,32]. Besides, we did not include patients with delayed ejaculation to compare with.…”

Impact of Targeting β3 Receptor on Male Sex Hormonal Balance

“…The authors have found that there is a significant decrease in androgen levels in mice lacking adrenergic receptors. Regarding α-adrenoceptors, it is known that these receptors have a significant impact on the control of sexual behavior [36], [37], [38]. A recent review highlighted the important link between androgens and the adrenergic system in both health and disease states [39].…”