Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Abstract

Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2Ј-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity.

Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice

“…In contrast, there are only a few reports on the effects of FLX on neurogenesis in the SVZ [2,9,10,[15][16][17][18]. Almost all of the studies in the literature have revealed no influence of FLX on neurogenesis in the SVZ.…”

“…Almost all of the studies in the literature have revealed no influence of FLX on neurogenesis in the SVZ. In the experiments, the authors administered FLX for 2 to 4 weeks as a chronic treatment model, and the time courses that the authors used in the experiments on neurogenesis in the SVZ were the same as those in the DG [2,9,10,[15][16][17][18]. Considering that 5-HT-containing fibers and 5-HT receptor subtypes can be detected in the SVZ [19] and that a pharmacological experiment with agonists and antagonists of 5-HT receptor subtypes suggested that 5-HT regulates neurogenesis in the SVZ [19], we hypothesized that FLX has a late-onset effect on neurogenesis in the SVZ.…”

Sex differences in animal models of psychiatric disorders

“…Also, often, treatment response is affected by sex-dependent differences in baseline behaviour, whereas the response to psychotropic drugs masks sex differences post-treatment. Importantly, sex differences in response to psychotropic drugs, are often related to pharmacokinetic sex differences and this should be taken into account when results from animal and human studies are interpreted (Nabeshima et al, 1984; Andine et al, 1999;Shelnutt et al, 1999;Hodes et al, 2010;Kokras et al, 2011a).…”

“…Also, often, treatment response is affected by sex-dependent differences in baseline behaviour, whereas the response to psychotropic drugs masks sex differences post-treatment. Importantly, sex differences in response to psychotropic drugs, are often related to pharmacokinetic sex differences and this should be taken into account when results from animal and human studies are interpreted (Nabeshima et al, 1984; Andine et al, 1999;Shelnutt et al, 1999;Hodes et al, 2010;Kokras et al, 2011a).Behavioural sex differences usually result from sex differences in neural underpinnings and/or are linked with sex differences in brain structure, neurochemistry, neuroendocrinology and neurobiology (Cahill, 2006;Cosgrove et al, 2007;Solomon and Herman, 2009). Sex differences result from chromosome effects, organizational effects of sex hormones during development of the brain and/or activational effects of sex hormones (McCarthy et al, 2012).…”

Third Trimester Fetal Heart Rate and Doppler Middle Cerebral Artery Blood Flow Velocity Characteristics During Prenatal Selective Serotonin Reuptake Inhibitor Exposure

“…During brain development, serotonin acts as a regulatory factor influencing cell proliferation, migration, and differentiation. Thus, SSRIelicited alterations in brain serotonin levels could affect these processes; hence, prenatal SSRI exposure in rats alters cell proliferation and survival in multiple areas of the fetal brain (39). Second, there could be systemic effects of transient increases in blood serotonin associated with each daily SSRI dose, resulting in repetitive bouts of reduced uterine blood flow and fetal hypoxemia, which could lead to a redistribution of fetal cardiac output as well as endocrine and metabolic changes affecting fetal growth, brain development, and gestation length (38,40).…”