Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine

Elizabeth A Pekarskaya,Mark S Ansorge,Jay A Gingrich,Emma S Holt,Sarah E Canetta,Jonathan A Javitch

doi:10.1038/s41598-021-02074-9

Abstract

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.

Highlights

To determine whether the paradoxical anxiogenic response to chronic FLX in PNFLX mice was the result of early FLX exposure, as opposed to a general result for mice on a C57 background, we examined the effects of chronic adult FLX administration on latency to feed in the Novelty suppressed feeding (NSF) in PNFLX, PNVEH, and naïve mice on a 129 background
We examined whether chronic TIA would improve avoidant behaviors in the NSF in PNFLX mice, as a separate measure of avoidant behavior that would not be as influenced by changes in overall locomotion
We found that PNFLX C57 mice showed decreased novelty-induced exploration and increased avoidant behavior, similar to effects seen in PNFLX 129 mice

Summary

Introduction

In the current study, we find that these avoidant symptoms are not responsive to subsequent SSRI administration in adulthood These findings may have implications for the children of those who take SSRIs while pregnant. MOR activation is responsible for both the analgesic and addictive effects of opioid pain relievers such as morphine, at clinical doses TIA does not promote euphoria and has been considered as a viable alternative to frontline treatments that directly target monoaminergic systems for treatment-resistant d epression. Our study is designed to assess and compare the efficacy of FLX versus TIA in a mouse model of gestational SSRI exposure, which may have broader implications for affective disorder subtypes with a shared etiology that are resistant to SSRI treatment

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