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.

Keywords: agomelatine; dopaminergic system; immunohistochemical study; male rats; paroxetine; sexual dysfunction.

Figure 1

(A–C). Tyrosine hydroxylase immunoreactivity in the meso-diencephalic dopaminergic system of rats from the control (A), paroxetine (B), and agomelatine (C) groups. Bars, 100 m. SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulate; VTA, ventral tegmental area; MT, mammilothalamic tract.

Figure 2

(A–F). Tyrosine hydroxylase immunoreactivity in the striatum of control rats (A,D), and rats treated with paroxetine (B,E) and agomelatine (C,F). Bars 1000 m (A–C) and 100 m (D–F). The reactivity is visible as dotted labeling that is evenly distributed by the matrix of the caudate-putamen (CPu), except in paroxetine-treated rats. CC, corpus callosum; latV, lateral ventriculum; AC, anterior commissure; Acc, nucleus accumbens; Estr, striatum; Sept, septum.

Figure 3

(A–C). Tyrosine hydroxylase immunoreactivity in the hippocampus of rats from the control (A), paroxetine (B), and agomelatine (C) groups. Bars, 1000 m. (Figure 3A is presented at the same magnification as that of Figure 3B,C). The immunoreactivity is limited to the CA3 area and is greatly reduced following treatment with paroxetine. DG, dentate gyrus; CA, cornu ammonis.

Figure 4

(A–C). Tyrosine hydroxylase immunoreactivity in the cerebral cortex layers I-VI of rats from the control (A), paroxetine (B), and agomelatine (C) groups. Bars, 1000 m. (Figure 4A is presented at the same magnification as that of Figure 4B,C). CM/S, motor/somatosensory cortex.

Figure 5

(A–C). Tyrosine hydroxylase immunoreactivity in the zona incerta of rats from the control (A), paroxetine (B), and agomelatine (C) groups. Bars, 100 m. In the rats treated with paroxetine, the labeling is weak whereas in animals treated with agomelatine, labeling is similar to that shown the control rats. IIIV, third ventricle; ZI, zona incerta.

Figure 6

(A–C). Tyrosine hydroxylase immunoreactivity in the mediobasal hypothalamus of rats from the control (A), paroxetine (B), and agomelatine (C) groups. Bars, 1000 m. After treatment with paroxetine, TH immunoreactivity is absent from the median eminence. ARCN, arcuate nucleus; ME, median eminence; IIIV, third ventricle; VMN, ventromedial nucleus.

Figure 7

Pixel intensity was determined using open source software ImageJ. There are significant differences between all groups in the SNc, but no statistical difference between the control group and rats treated with agomelatine in the VTA.