Understanding the Mechanism of Antidepressant-Related Sexual Dysfunction: Inhibition of Tyrosine Hydroxylase in Dopaminergic Neurons after Treatment with Paroxetine but Not with Agomelatine in Male Rats

Abstract

Antidepressant-related sexual dysfunction is a frequent adverse event caused by serotonergic activation that intensely affects quality of life and adherence in depressed patients. The dopamine system has multiple effects promoting sexual behavior, but no studies have been carried out to confirm dopaminergic changes involved in animal models after antidepressant use. Methods: The sexual behavior-related dopaminergic system in the rat was studied by comparing two different antidepressants and placebo for 28 days. The antidepressants used were paroxetine (a serotonergic antidepressant that causes highly frequent sexual dysfunction in humans) and agomelatine (a non-serotonergic antidepressant without associated sexual dysfunction). The tyrosine hydroxylase immunoreactivity (THI) in the substantia nigra pars compacta, the ventral tegmental area, the zona incerta, and the hypothalamic arcuate nucleus, as well as the dopaminergic projections to the striatum, hippocampus, cortex, and median eminence were analyzed. Results: The THI decreased significantly in the substantia nigra and ventral tegmental area after treatment with paroxetine, and the labeling was reduced drastically in the zona incerta and mediobasal hypothalamus. The immunoreactive axons in the target regions (striatum, cortex, hippocampus, and median eminence) almost disappeared only in the paroxetine-treated rats. Conversely, after treatment with agomelatine, a moderate reduction in immunoreactivity in the substantia nigra was found without appreciable modifications in the ventral tegmental area, zona incerta, and mediobasal hypothalamus. Nevertheless, no sexual or copulatory behavior was observed in any of the experimental or control groups. Conclusion: Paroxetine but not agomelatine was associated with important decreased activity in dopaminergic areas such as the substantia nigra and ventral tegmental areas that could be associated with sexual performance impairment in humans after antidepressant treatment.

Kisspeptin and RF9 prevent paroxetine‐induced changes in some parameters of seminal vesicle fluid in the male rats

“…Agomelatine's psychotropic effects are caused by the synergy between the melatonergic and 5-HT 2 C receptor features (Racagni et al, 2011). It was reported in previous studies that unlike SSRIs, agomelatine does not cause serious adverse effects on sexual function (Santana et al, 2019) or sperm parameters (Elnazer & Baldwin, 2014).…”

Frequency of Sexual Dysfunction in Patients Treated with Desvenlafaxine: A Prospective Naturalistic Study

“…The lower pharmacodynamic potency in the reuptake of serotonin compared to venlafaxine might be linked to the lower effect in the dopaminergic brake, mediated by serotonin, associated with sexual dysfunction. Recently, it has been shown that paroxetine, a potent inhibitor of serotonin reuptake, influences the mechanism of AD-related sexual dysfunction through the inhibition of tyrosine hydroxylase in dopaminergic neurons related to sexual areas such as substantia nigra, pars compacta, and the ventral tegmental area but not with agomelatine in male rats [46].…”

Serotonergic, Dopaminergic, and Noradrenergic Modulation of Erotic Stimulus Processing in the Male Human Brain

“…Although the stimulation of some specific serotonin receptor subtypes, e.g., 5-HT 2c - or 5-HT 1A -receptors, may facilitate erection or ejaculation, primary central serotonergic effects are thought to be inhibitory. These effects are presumably mediated via decreased dopamine release in mesolimbic regions [28,36] and by suppressing spinal ejaculatory centers [37]. Accordingly, up to 80% of patients treated with the SSRI sertraline report sexual dysfunction and, in particular in young patients, antidepressant-related decrease in sexual function is one of the most relevant side effects [24,38].…”