Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose–response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a μ-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT-/- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as “on demand” therapy for PE.

Near-infrared spectroscopy (NIRS) is a non-invasive technique for measuring regional tissue haemoglobin (Hb) concentrations and oxygen saturation (rSO2). It may be used to monitor cerebral perfusion and oxygenation in patients at risk of cerebral ischemia or hypoxia, for example, during cardiothoracic or carotid surgery. However, extracerebral tissue (mainly scalp and skull tissue) influences NIRS measurements, and the extent of this influence is not clear. Thus, before more widespread use of NIRS as an intraoperative monitoring modality is warranted, this issue needs to be better understood. We therefore conducted a systematic review of published in vivo studies of the influence of extracerebral tissue on NIRS measurements in the adult population. Studies that used reference techniques for the perfusion of the intra- and extracerebral tissues or that selectively altered the intra- or extracerebral perfusion were included. Thirty-four articles met the inclusion criteria and were of sufficient quality. In 14 articles, Hb concentrations were compared directly with measurements from reference techniques, using correlation coefficients. When the intracerebral perfusion was altered, the correlations between Hb concentrations and intracerebral reference technique measurements ranged between |r| = 0.45–0.88. When the extracerebral perfusion was altered, correlations between Hb concentrations and extracerebral reference technique measurements ranged between |r| = 0.22–0.93. In studies without selective perfusion modification, correlations of Hb with intra- and extracerebral reference technique measurements were generally lower (|r| < 0.52). Five articles studied rSO2. There were varying correlations of rSO2 with both intra- and extracerebral reference technique measurements (intracerebral: |r| = 0.18–0.77, extracerebral: |r| = 0.13–0.81). Regarding study quality, details on the domains, participant selection and flow and timing were often unclear. We conclude that extracerebral tissue indeed influences NIRS measurements, although the evidence (i.e., correlation) for this influence varies considerably across the assessed studies. These results are strongly affected by the study protocols and analysis techniques used. Studies employing multiple protocols and reference techniques for both intra- and extracerebral tissues are therefore needed. To quantitatively compare NIRS with intra- and extracerebral reference techniques, we recommend applying a complete regression analysis. The current uncertainty regarding the influence of extracerebral tissue remains a hurdle in the clinical implementation of NIRS for intraoperative monitoring. The protocol was pre-registered in PROSPERO (CRD42020199053).

Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT 1A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT 1A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT 1A autoreceptors and postsynaptic 5-HT 1A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT −/−) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT 1A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT 1A receptors in the pro-sexual effects of 5-HT 1A receptor agonists in SERT +/+ and in SERT −/− rats. Therefore, acute effects of the biased 5-HT 1A receptor agonists F-13714, a preferential 5-HT 1A autoreceptor agonist, or F-15599, a preferential 5-HT 1A heteroreceptor agonist, and S15535 a mixed 5-HT 1A 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-HT 1A auto-and hetero-receptors, exerted pro-sexual activity in both SERT +/+ and

Rationale Many depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior. Objectives Our aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring. Methods Heterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2–15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed. Results Perinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring. Conclusions Overall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

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