Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5‐HT_1Aand 5‐HT_1Breceptor agonists 8‐OH‐DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD‐299 and NAS‐181

Abstract

1 Ejaculatory problems and anorgasmia are well-known side-e ects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT 1A and 5-HT 1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes. 2 The 5-HT 1A receptor agonist 8-OH-DPAT (0.25 ± 4.00 mmol kg 71 s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this e ect was fully antagonized by pretreatment with the new selective 5-HT 1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-¯uoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 mmol kg 71 s.c.). NAD-299 by itself (0.75 ± 3.00 mmol kg 71 s.c.) did not a ect the male rat ejaculatory behaviour. 3 The 5-HT 1B receptor agonist anpirtoline (0.25 ± 4.00 mmol kg 71 s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this e ect was fully antagonized by pretreatment with the 5-HT 1B receptor antagonist isamoltane (16 mmol kg 71 s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorpholino methansulphonate (NAS-181) (16 mmol kg 71 s.c.). Isamoltane (1.0 ± 16.0 mmol kg 71 s.c.) and NAD-181 (1.0 ± 16.0 mmol kg 71 s.c.) had no, or weakly facilitatory e ects on the male rat ejaculatory behaviour. The non-selective 5-HT 1 receptor antagonist (7)-pindolol (8 mmol kg 71 s.c.), did not antagonize the inhibition produced by anpirtoline.4 The present results demonstrate opposite e ects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT 1A and 5-HT 1B receptors, respectively, suggesting that the SSRIinduced inhibition of male ejaculatory dysfunction is due to 5-HT 1B receptor stimulation.

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

“…It was particularly noteworthy in individuals that show high levels of aggression as a result of social instigation or alcohol treatment (Fish et al .1999;de Almeida et al 2001;Rilke et al 2001). In addition, anpirtoline inhibits anxiety-like and depression-like behaviors, pain, and sexual behavior (Schlicker et al 1992;Metzenauer et al 1992;Hillegaart and Ahlenius 1998;Bouwknecht et al 2001;O'Neill and Conway 2001). The reduction in aggression was antagonized by GR127935, indicated by a rightward shift in the doseeffect curves of anpirtoline, demonstrating the 5-HT 1B receptors as the key site of action.…”

“…Agonists at postsynaptic 5-HT 1B receptors, such as CP-94,253, zolmitriptan, and anpirtoline, produce remarkably specific inhibition of species-typical aggression and very intense and frequent aggressive behavior at doses that do not alter the remaining behavioral repertoire (Fish et al 1999;de Almeida et al 2001;Miczek and de Almeida 2001). At higher 5-HT 1B receptor agonist doses sexual and alimentary behavior is suppressed and motor behavior stimulated (Hillegaart and Ahlenius 1998;Lee et al 1998;Stenfors et al 2000). Anpirtoline, a 5-HT 1B agonist, has been shown to have a high affinity for 5-HT 1B receptors (K(i) ϭ 28 nM) (Schlicker et al 1992;Swedberg et al 1992).…”

Pharmacology for the Treatment of Premature Ejaculation

“…Agonists of 5HT1B receptors impair ejaculation when given systemically to male rats free to copulate (Fernán-dez-Guasti et al, 1992;Hillegaart and Ahlenius, 1998). Moreover, blockade of 5-HT1B receptors reverses the inhibitory action of the 5-HT metabolite precursor 5-hydroxytryptophan on ejaculation (Ahlenius and Larsson, 1998).…”

“…The 5-HT1A-selective agonist 8-OH-DPAT has a facilitator effect on ejaculation after systemic delivery in rats (Hillegaart and Ahlenius, 1998;Rowland and Houtsmuller, 1998). This proejaculatory activity was observed after microinjection of 8-OH-DPAT into the median raphe nucleus or nucleus accumbens (Hillegaart et al, 1991;Ferná ndez-Guasti et al, 1992).…”

Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-Hydroxytryptamine 1B Receptor Antagonist

“…The presynaptic 5-HT 1B autoreceptor also regulates 5-HT release, so it has been considered as an alternative target to 5-HT reuptake transporters for antidepressants (Gaster et al, 1998;Hillegaart and Ahlenius, 1998;Roberts et al, 2001;Ahlgren et al, 2004;Dawson et al, 2006). This mechanism also has the potential to provide a rapid onset of clinical efficacy without the liabilities associated with SSRIs (Moret and Briley, 2000;Slassi, 2002).…”