Delay of ejaculation induced by SB-277011, a selective dopamine D3 receptor antagonist, in the rat.
BACKGROUND
Dopamine (DA) plays a key role in different aspects of the male sexual response, including sexual motivation and arousal, penile erection, and ejaculation. The modalities of action of DA are however unclear, although the various DA receptors may differentially mediate the activity of DA in different aspects of the male sexual response.


OBJECTIVE
To clarify the role of DA D(3) receptors in the control of the male sexual response.


METHODS
The effects of a highly selective DA D(3) receptors antagonist (SB-277011; intraperitoneal) were tested in experimental paradigms exploring several aspects of the male sexual response in (i) anesthetized rats using 7-hydroxy-N,N-di-n-propylaminotetralin to induce ejaculation and (ii) conscious rats using sexual incentive motivation and mating tests.


METHODS
Physiological markers of erection and emission and expulsion phases of ejaculation were measured in anesthetized rats. Behavioral parameters of sexual incentive motivation and mating tests were quantified.


RESULTS
In anesthetized rats, we found that SB-277011 specifically and dose-dependently inhibited the expulsion phase of ejaculation without impairing either emission phase or erection, and this resulted in delayed ejaculation. Administration of SB-277011 had no effect on the spontaneous preference that males displayed for sexually receptive females as shown in sexual incentive motivation test. Delayed ejaculation was confirmed when male rats were administered with the highest dose of SB-277011 (10 mg/kg) in mating test, where males were free to copulate with estrous females. In addition, the refractory period following ejaculation was lengthened in rats treated with SB-277011.


CONCLUSIONS
As a whole, the present data demonstrate the specific and primary role of D(3) receptors in the expulsion phase of ejaculation and provide preclinical evidence for the investigation of the therapeutic potential of D(3) antagonism for treating premature ejaculation.
Clément
Pierre
P
Pelvipharm Laboratories, Orsay, France.
Pozzato
Chiara
C
Department of Biology, Centre of Excellence in Drug Discovery, GlaxoSmithKline S.p.A., Verona, Italy.
Heidbreder
Christian
C
Department of Biology, Centre of Excellence in Drug Discovery, GlaxoSmithKline S.p.A., Verona, Italy.
Alexandre
Laurent
L
Pelvipharm Laboratories, Orsay, France.
Giuliano
Francois
F
Pelvipharm Laboratories, Orsay, France;; Neuro-Uro-Andrology Unit, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France. Electronic address: giuliano@cyber-sante.org.
Melotto
Sergio
S
Department of Biology, Centre of Excellence in Drug Discovery, GlaxoSmithKline S.p.A., Verona, Italy.
D000818:Animals; D004542:Ejaculation / Q000187:drug effects*; D004576:Electromyography; D005260:Female; D008297:Male; D009130:Muscle, Smooth / Q000294:innervation; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012726:Sexual Behavior, Animal; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D009570:Nitriles; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines