Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with Abnormal 5-HT_1A Receptor Functional Activity

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Anton S. Tsybko^1,a#*, Elena M. Kondaurova^1#, Elena A. Zalivina¹, Varvara O. Blaginya¹, and Vladimir S. Naumenko¹

¹Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to this work.

Received March 15, 2023; Revised April 11, 2023; Accepted April 12, 2023

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The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT_1A receptors and upregulated 5-HT_1A gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced the pro-depressive effect in a forced swim test. Since 5-HT_2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT_2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT_1A and 5-HT_2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine, while fluoxetine, ketanserin, and fluoxetine + ketanserin decreased the functional activity of 5-HT_1A receptors and Htr1a gene transcription in the midbrain and hippocampus. All tested drug regimens decreased the mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT_2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT_1A receptors.

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KEY WORDS: 5-HT_1A receptor, 5-HT_2A receptor, TPH2, fluoxetine, ketanserin, antidepressant resistance

DOI: 10.1134/S0006297923060044

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