Tramadol’s Inhibitory Effects on Sexual Behavior: Pharmacological Studies in Serotonin Transporter Knockout Rats

Abstract

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.

Antidepressants and Sexual Dysfunctions: a Translational Perspective

“…1a). From the second test on, SERT+/+ and SERT+/− ejaculate more than SERT−/− rats, confirming earlier findings [62,92]. Figure 1b shows the distribution of animals with zero to five ejaculations during the last (sixth) training test.…”

“…SERT−/− rats, like SERT−/− mice, show disturbed serotonergic systems and various behavioral (e.g., exploration, aggression, nociception, anxiety, fear) and physiological changes (e.g., temperature regulation, sleep), largely due to (disturbed) developmental processes [91]. Interestingly, male SERT−/− rats have a lower basal level of sexual behavior than SERT+/+ rats [62,92].…”

“…In normal rats, tramadol acutely inhibited male sexual behavior, mainly due to its SSRI-properties, although some μ-opioid receptor stimulation was involved [61]. Tramadol in SERT−/− rats still inhibited sexual behavior, but extensive pharmacological studies involving 5-HT 1A -receptor and μ-opioid receptor antagonism and combined blocking of both receptors did not yet completely unravel the probable underlying sexual inhibiting mechanism of tramadol, apart from its SSRI mechanism [62].…”

Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats

“…This can also be illustrated by the comparable ejaculation curves (# ejaculations after training) for both genotypes of which the SERT −/− rats are shifted to the left compared to the SERT +/+ rats . The typical distribution patterns of the # of ejaculations (or the 1st ejaculation latency times) in a large cohort of SERT-genotypes supplies us with the possibility to behaviorally match animals with a certain genotype, e.g., only high versus low sexually performing animals, as we did previously in the study of tramadol effects on male sexual behavior (Esquivel-Franco et al, 2018). Supplementary Table 4.…”

“…The exact mechanisms for these dysfunctions remain unclear, but are high likely due to alterations in the 5-HT 1A receptor. Male rats lacking the serotonin transporter (SERT −/− ) display a robust genotype that has a lower basal ejaculatory performance than wildtype rats (SERT +/+ ) or heterozygous serotonin transporter knockout (SERT +/− ) rats (Chan et al, 2011;Esquivel-Franco et al, 2018). More specific, due to the lack of the serotonin transporter SERT −/− rats have a nine-fold increase in extracellular 5-HT levels (Homberg et al, 2007), decreased number of ejaculations and an increased ejaculation latency (Chan et al, 2011) compared to SERT +/+ rats.…”