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Pharmacological Studies on the Role of 5-HT1 A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats.

ABSTRACT: Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT1 A autoreceptors and postsynaptic 5-HT1 A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT-/-) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT1 A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT1 A receptors in the pro-sexual effects of 5-HT1 A receptor agonists in SERT+/+ and in SERT-/- rats. Therefore, acute effects of the biased 5-HT1 A receptor agonists F-13714, a preferential 5-HT1 A autoreceptor agonist, or F-15599, a preferential 5-HT1 A heteroreceptor agonist, and S15535 a mixed 5-HT1 A autoreceptor agonist/heteroreceptor antagonist, on male sexual behavior were assessed. A clear and stable genotype effect was found after training where SERT+/+ performed sexual behavior at a higher level than SERT-/- rats. Both F-15599 and F-13714 induced pro-sexual activity in SERT+/+ and SERT-/- animals. Compared to SERT+/+, the F13714-dose-response curve in SERT-/- rats was shifted to the right. SERT+/+ and SERT-/- rats responded similar to F15599. Within both SERT+/+ and SERT-/- rats the potency of F-13714 was much stronger compared to F-15599. S15535 had no effect on sexual behavior in either genotype. In SERT+/+ and SERT-/- rats that were selected on comparable low sexual activity (SERT+/+ 3 or less ejaculations and SERT-/- 5 or less ejaculations in 10 weeks) S15535 also did not influence sexual behavior. The two biased compounds with differential effects on 5-HT1 A auto- and hetero-receptors, exerted pro-sexual activity in both SERT+/+ and SERT-/- rats. Applying these specific pharmacological tools has not solved whether pre- or post-synaptic 5-HT1 A receptors are involved in pro-sexual activity. Moreover, the inactivity of S15535 in male sexual behavior in either genotype was unexpected. The question is whether the in vivo pharmacological profile of the different 5-HT1 A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT1 A receptor contributions in male rat sexual behavior.

SUBMITTER: Esquivel-Franco DC

PROVIDER: S-EPMC7136541 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pharmacological Studies on the Role of 5-HT1 A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats.

Esquivel-Franco Diana Carolina DC de Boer Sietse F SF Waldinger Marcel M Olivier Berend B Olivier Jocelien D A JDA

Frontiers in behavioral neuroscience 20200331

Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT1 A autoreceptors and postsynaptic ...[more]

PMID: 32296313

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Project description:Central dopamine plays a key role in sexual behavior. Recently, a Dopamine Transporter knockout (DAT KO) rat has been developed, which displays several behavioral dysfunctions that have been related to increased extracellular dopamine levels and altered dopamine turnover secondary to DAT gene silencing. This prompted us to characterize the sexual behavior of these DAT KO rats and their heterozygote (HET) and wild type (WT) counterparts in classical copulatory tests with a sexually receptive female rat and to verify if and how the acquisition of sexual experience changes along five copulatory tests in these rat lines. Extracellular dopamine and glutamic acid concentrations were also measured in the dialysate obtained by intracerebral microdialysis from the nucleus accumbens (Acb) shell of DAT KO, HET and WT rats, which underwent five copulatory tests, when put in the presence of an inaccessible sexually receptive female rat and when copulation was allowed. Markers of neurotropism (BDNF, trkB), neural activation (?-FosB), functional (Arc and PSA-NCAM) and structural synaptic plasticity (synaptophysin, syntaxin-3, PSD-95) were also measured in the ventral tegmental area (VTA), Acb (shell and core) and medial prefrontal cortex (mPFC) by Western Blot assays. The results indicate that the sexual behavior of DAT KO vs. HET and WT rats shows peculiar differences, mainly due to a more rapid acquisition of stable sexual activity levels and to higher levels of sexual motivation and activity. These differences occurred with differential changes in dopamine and glutamic acid concentrations in Acb dialysates during sexual behavior, with lower increases of dopamine and glutamic acid in DAT KO vs. WT and HET rats, and a lower expression of the markers investigated, mainly in the mPFC, in DAT KO vs. WT rats. Together these findings confirm a key role of dopamine in sexual behavior and provide evidence that the permanently high levels of dopamine triggered by DAT gene silencing cause alterations in both the frontocortical glutamatergic neurons projecting to the Acb and VTA and in the mesolimbic dopaminergic neurons, leading to specific brain regional changes in trophic support and neuroplastic processes, which may have a role in the sexual behavior differences found among the three rat genotypes.

Project description:The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45β, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

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Pharmacological Studies on the Role of 5-HT1 A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats.

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Pharmacological Studies on the Role of 5-HT<sub>1</sub> <sub>A</sub> Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats.

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