Serotonin transporter inhibition during neonatal period induces sex‐dependent effects on mitochondrial bioenergetics in the rat brainstem

Abstract

The serotonin reuptake is mainly regulated by the serotonin transporters (SERTs), which are abundantly found in the raphe nuclei, located in the brainstem. Previous studies have shown that dysfunction in the SERT has been associated with several disorders, including depression and cardiovascular diseases. In this manuscript, we aimed to investigate how gender and the treatment with a serotonin selective reuptake inhibitor (SSRI) could affect mitochondrial bioenergetics and oxidative stress in the brainstem of male and female rats. Fluoxetine, our chosen SSRI, was used during the neonatal period (i.e., from postnatal Day 1 to postnatal Day 21-PND1 to PND21) in both male and female animals. Thereafter, experiments were conducted in adult rats (60 days old). Our results demonstrate that, during lactation, fluoxetine treatment modulates the mitochondrial bioenergetics in a sex-dependent manner, such as improving male mitochondrial function and female antioxidant capacity.

Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2Areceptor and SIRT1–PGC-1α axis

“…In cardiomyocytes, 5-HT promotes cell survival via the 5-HT 2B receptor and PI3K–Akt and MAPK pathways (15). Perinatal selective serotonin reuptake inhibitor exposure is linked to increased mitochondrial respiratory capacity and reduced ROS levels in cardiac tissue (16) and liver (17), as well as sex-specific effects on brainstem mitochondrial function (18). Thus far, few studies have examined the direct influence of 5-HT on mitochondria in neurons.…”

Maternal Protein Restriction in Two Successive Generations Impairs Mitochondrial Electron Coupling in the Progeny’s Brainstem of Wistar Rats From Both Sexes

“…Among the factors contributing to the degree of oxidative damage, and conversely the upregulation of antioxidant defenses in individuals exposed to malnutrition during gestation/lactation, is the gender, which greatly influences the relative amount of estrogen present both during the period of mitochondrial damage in the mother, and later in life when damage first becomes evident in the progeny (Lagranha et al, 2010; Braz et al, 2017; Silva et al, 2018). Clearly then, a maternal low-protein diet would be expected to affect male and female offspring differently in the F1 generation, and perhaps into succeeding generations.…”

Effects of fluoxetine withdrawal in the brainstem and hypothalamus of overnourished rats: Chronic modulation on oxidative stress levels

“…Previous data in the literature showed positive impacts of serotonergic manipulation in overnourished young rats de Andrade Silva et al, 2022;Silva et al, 2019). Our present study is different from previous studies from our laboratory Braz et al, 2016;da Silva et al, 2014da Silva et al, , 2015Silva et al, 2018Silva et al, , 2019, since we focus on understanding the long-lasting effect of the fluoxetine, 30 days after the treatment withdraw.…”