5-HT(2C) receptor activation is a common mechanism on proerectile effects of apomorphine, oxytocin and melanotan-II in rats.
5-Hydroxytryptamine (5-HT), dopamine, oxytocin and melanocortin pathways are known to be involved in the induction of penile erections in rats. Although a dopamine-oxytocin-5-HT link in the central nervous system has been suggested to be important to the control of penile erections, the 5-HT receptor subtype that mediates dopamine-oxytocin-5-HT action and the relationship between the dopamine-oxytocin-5-HT pathway and melanocortin pathway have not been fully elucidated. In this study, in order to clarify these matters, we examined the effects of a selective 5-HT(2B)/5-HT(2C) receptors antagonist, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea (SB200646) and a selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline (SB242084) on penile erections induced by a dopamine receptor agonist, 10, 11-dihydroxyaporphine (apomorphine), oxytocin, or a melanocortin receptor agonist, melanotan-II (MT-II) in rats. SB200646 at 10 mg/kg and SB242084 at 3 mg/kg, these doses which completely antagonize penile erections induced by 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), significantly inhibited penile erections elicited by apomorphine, oxytocin or MT-II. In addition, in order to clarify further the suggestion that the 5-HT pathway projecting from medulla oblongata to lumbosacral spinal site and lumbosacral 5-HT(2C) receptor are involved in the induction of penile erection, we also examined the proerectile effect of YM348 in spinal and a 5-HT depletor, p-chlorophenyl alanine (pCPA)-treated rats. YM348 induced intracavernous pressure increase in spinal and pCPA-treated rats as well as normal rats. These results suggest that 5-HT(2C) receptor in lumbosacral spinal sites mediates not only dopamine-oxytocin-5-HT action but melanocortin action on penile erections, and that the 5-HT pathway is located downstream from melanocortin pathway as well as the dopamine-oxytocin pathway.
Kimura
Yasuharu
Y
Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki, Japan. yasuharu.kimura@jp.astellas.com <yasuharu.kimura@jp.astellas.com>
Naitou
Yuki
Y
Wanibuchi
Fumikazu
F
Yamaguchi
Tokio
T
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008161:Lumbosacral Region; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D010121:Oxytocin / Q000494:pharmacology*; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000294:innervation*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D018491:Dopamine Agonists; D007191:Indazoles; D007211:Indoles; D010456:Peptides, Cyclic; D010879:Piperazines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C488691:YM348; C079282:melanotan-II; C080864:N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea; D010121:Oxytocin; D000521:alpha-MSH; D014508:Urea; D001058:Apomorphine; C015068:1-(3-chlorophenyl)piperazine