Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine.

Elena M Kondaurova,Dmitry V Eremin,Yegor V Antonov,Nina K Popova,Alexander Ya Rodnyy,Vladimir S Naumenko,Anton S Tsybko,Tatiana V Ilchibaeva

doi:10.3390/ijms21228784

Elena M Kondaurova, Dmitry V Eremin + Show 6 more

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https://doi.org/10.3390/ijms21228784

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Abstract

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73–110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

Highlights

Depression is the one of the most common human mental disorders, significantly reducing the quality of life
The B6-M76C mice were differed by 5-HT1A receptor sensitivity to chronic activation with 5-HT1A receptor agonist 8-OH-DPAT, which allowed us to assume that B6-M76C mice have a genetically defined reduced sensitivity of presynaptic 5-HT1A receptor [31] and that these changes in genetic background can modulate the response to 5-HT1A-related antidepressants from the Selective Serotonin Reuptake Inhibitors (SSRIs) family. To further confirm this idea, we studied the effects of chronic treatment with the classical SSRI antidepressant fluoxetine on (i) behavior in the open field and forced swim tests; (ii) mRNA and protein levels for Freud-1, 5-HT1A, 5-HT2A and 5-HT7 receptors as well as TPH-2, MAOA and 5-HTT and (iii) 5-HT and 5-HIAA levels and 5-HIAA/5-HT ratio in the brain structures of B6-M76B and B6-M76C mouse lines
Taking into account that B6-M76B mice carry a C57BL/6 genetic background, our data are in general agreement with other studies that have reported marked strain and genotype dependence in response to SSRIs in a forced swim test [32,33,34,35,36]

Summary

Introduction

Depression is the one of the most common human mental disorders, significantly reducing the quality of life. A number of studies indicate the implication of the serotonin 5-HT1A receptor in the positive effect of chronically administered SSRIs [4]. These 5-HT1A receptors could be localized both pre- and postsynaptically. Receptor function is strongly dependent on localization: in the raphe nuclei of the midbrain, it acts as a presynaptic somatodendritic autoreceptor, inhibiting neuronal activity and 5-HT secretion into the synaptic cleft, whereas the postsynaptic 5-HT1A receptor mediates 5-HT action on neurons. There is some evidence indicating the role of presynaptic 5-HT1A receptors in the mechanism of antidepressant drug action [10,15,16]. Selective overexpression of postsynaptic 5-HT1A receptors is associated with a clear-cut antidepressant response to the SSRI citalopram [20]

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