Fluoxetine effects on behavior and adult hippocampal neurogenesis in female C57BL/6J mice across the estrous cycle

Abstract

Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle.Several studies have demonstrated that chronic antidepressant treatment can decrease anxietylike behaviors and increase adult hippocampal neurogenesis in male rodents. However, very few studies have conclusively looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents. Here we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle. Interestingly, we find that the effects of fluoxetine on both behavior and adult hippocampal neurogenesis are driven by mice specifically in the estrus or diestrus phases of the estrous cycle. Taken together our data is the first to illustrate the impact of fluoxetine on brain and behavior across all four stages of the murine estrous cycle. Highlights:• Chronic fluoxetine reduces anxiety-like behaviors in naturally cycling female mice • Chronic fluoxetine increases adult hippocampal neurogenesis in naturally cycling female mice • The effects of chronic fluoxetine on behavior and adult hippocampal neurogenesis are driven by the estrus and diestrus phases of the estrous cycle

Inactivation of the GATA Cofactor ZFPM1 Results in Abnormal Development of Dorsal Raphe Serotonergic Neuron Subtypes and Increased Anxiety-Like Behavior

“…Chronic fluoxetine treatment reverses the increased contextual fear memory in the Zfpm1 CKO mice Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are used as antidepressants that increase the serotonin level in the synapses by inhibiting its reuptake into presynaptic serotonergic neurons via serotonin transporter SLC6A4 (Vaswani et al, 2003). Previous experiments in mice demonstrated fluoxetine treatment (3 weeks) facilitates fear erasure (Karpova et al, 2011;Sanders and Mayford, 2016;Yohn et al, 2018). Thus, control and Zfpm1 CKO female animals (only females were used as they were conditioned normally in the CFC experiment; see above) received fluoxetine (15 mg/kg/d in drinking water) for 3 weeks.…”

β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

“…The results were more variable ( Figure S1 F) and did not reach statistical significance, possibly due to known effects of the estrus cycle on anxiety-related behaviors and anxiolytics’ efficacy. 16 We used the male mice data and FDA recommendations 17 , 18 to calculate the human equivalent dose (HED) as 486 mg and the recommended starting dose as 48.6 mg (considering a standard body weight of 60 kg). This dosage is well in the range (∼2 g per day) of plant sterol dietary supplementation typically administered for cholesterol management.…”

“…The different responsiveness of male versus female mice to β-sitosterol should also be examined in more detail, specifically the likely influence of estrus cycle or other hormonal events on the anxiolytic response. 16 Finally, the effects of chronic treatment with β-sitosterol remain to be elucidated and due to the hydrophobic nature of the drug will likely require testing by long-term supplementation in animal diets.…”

Effect of SSRI discontinuation on anxiety-like behaviours in mice

“…If this difference translated to the female mice used here, it would account for their reduced sensitivity to paroxetine. The stage of the estrous cycle of mice was also found to influence the behavioural response to fluoxetine treatment, with mice in the diestrus phase of the cycle being less sensitive the drug (Yohn et al, 2020). Furthermore, we cannot exclude the possibility that these differences reflect different home cage experiences of male and female mice, particularly in terms of aggressive behaviours and social dominance hierarchies.…”