Miguel Laurin

Role of the Neurokinin-1 Receptors in Ejaculation in Anesthetized Rats

INTRODUCTION Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. AIM The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. METHODS Ejaculation was induced in anesthetized rats by intracerebroventricular (i.c.v.) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (i.p.), i.c.v., or intrathecal (i.t.) (third lumbar spinal segment; L3) administration. MAIN OUTCOME MEASURES Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. RESULTS Upon i.p., i.c.v., or i.t. administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following i.c.v. or i.t. administration. CONCLUSION These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors.

Effect of Dapoxetine on Ejaculatory Performance and Related Brain Neuronal Activity in Rapid Ejaculator Rats

INTRODUCTION A brain network specifically activated when ejaculation occurs has been described in rats. Increasing serotonin (5-hydroxytryptamine [5-HT]) tone impairs ejaculation and chronic 5-HT selective serotonin reuptake inhibitors (SSRIs) are known to inhibit ejaculation. However, efficacy of acute treatment with SSRI varies from one compound to another. The SSRI dapoxetine has been reported to delay ejaculation when given on demand to men with premature ejaculation (PE), although the mechanism of action is unclear. Effects of acute SSRIs on activity of the brain ejaculation circuit in relation with ejaculation have never been examined. AIM To test the effects of acute administration of the short half-life SSRI dapoxetine on ejaculatory performance and activity in brain ejaculation circuit in rapid ejaculator rats taken as PE model. METHODS Standard copulatory test was used to attribute one sexual category (sluggish, middle, or rapid) to male rats on the basis of their ejaculatory performance. Parameters of sexual, including ejaculatory, behavior, and Fos level of expression in discrete brain areas were assessed in the three sexual categories and in rapid category following acute oral treatment with dapoxetine. MAIN OUTCOME MEASURES Ejaculation frequency (EF) and latency (EL) were measured as primary end points of ejaculatory behavior. Density of Fos-immunopositive cells in specific brain areas of brain stem, hypothalamus, and thalamus was determined as marker of neuronal activity. RESULTS EL and Fos level of expression in hypothalamic and thalamic structures were found related. Dapoxetine acute oral administration (300 mg/kg) to rapid ejaculator rats resulted in (i) diminution of ejaculatory performance (lengthened EL and decreased EF); and (ii) modulation of Fos level of expression in hypothalamic and thalamic nuclei of the brain ejaculatory circuit. CONCLUSION Acute treatment with dapoxetine, which reduced ejaculatory performance in rapid ejaculator rats, was also accompanied with changes in neuronal activity in components of the brain ejaculatory network.

A SELECTIVE NEUROKININ-1 RECEPTOR ANTAGONIST MODULATES PHARMACOLOGICALLY-INDUCED EJACULATION IN ANAESTHETISED MALE RATS

For this purpose, ejaculation was elicited by delivering the dopamine D3 receptor preferring agonist [R(+)7hydroxy-2-(di-N-propylamino)tetralin; 7-OH-DPAT] into the cerebral ventricle (i.c.v.). The effects of a non peptide NK1 antagonist (RP67580) administered via different routes [i.c.v., intrathecal (i.t.), i.v.] were tested on 7-OHDPAT-induced ejaculation. Pierre Clément1, Magali Peeters1, Jacques Bernabé1, Miguel Laurin1, Pierre Denys2, François Giuliano1,2*

BRAIN OXYTOCIN RECEPTOR BLOCKADE INHIBITS PHARMACOLOGICALLY INDUCED SEXUAL RESPONSES IN ANAESTHETISED MALE RATS

For this purpose, ejaculatory and erectile responses were elicited by delivering the dopamine D3 receptor preferring agonist [R(+)7-hydroxy-2-(di-N-propylamino)tetralin; 7-OH-DPAT] into the cerebral ventricle (i.c.v.). The effects of a peptide OT antagonist administered via different routes [i.c.v., intrathecal (i.t.), i.v.] were tested on 7-OH-DPAT-induced sexual responses. Pierre Clément1, Magali Peeters1, Jacques Bernabé1, Miguel Laurin1, Pierre Denys2, François Giuliano1,2*