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Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with
Anton S Tsybko1, Elena M Kondaurova2, Elena A Zalivina2
1Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. antoncybko@mail.ru.
Abstract:
The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT1A receptors and upregulated 5-HT1A 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-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A 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-HT1A 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-HT2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT1A receptors.
Insights
Ketanserin did not reverse fluoxetine's pro-depressive effects in mice with altered serotonin 1A (5-HT1A) receptor sensitivity. Both drugs impacted 5-HT1A receptor activity and gene transcription, but failed to improve depression-like behaviors.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- The B6.CBA-D13Mit76C mouse strain exhibits altered serotonin 1A (5-HT1A) receptor sensitivity and increased 5-HT1A gene transcription.
- Chronic fluoxetine treatment induced pro-depressive effects in this mouse model, suggesting a complex interaction within the serotonin system.
Purpose of the Study:
- To investigate the effects of ketanserin, a selective 5-HT2A receptor antagonist, alone and in combination with fluoxetine, on behavior and neurobiological markers in the B6.CBA-D13Mit76C mouse strain.
- To determine if 5-HT2A receptor blockade could mitigate the pro-depressive effects of fluoxetine in this specific genetic background.
Main Methods:
- Chronic (14-day) intraperitoneal administration of ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or a combination of both drugs.
- Assessment of behavioral responses (forced swim test), functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and gene transcription of key serotonin system components in the brain.
Main Results:
- Ketanserin did not reverse the pro-depressive effect of fluoxetine.
- Fluoxetine, ketanserin, and their combination reduced 5-HT1A receptor functional activity and Htr1a gene transcription in the midbrain and hippocampus.
- All treatment groups decreased Slc6a4 and Maoa mRNA levels in the midbrain, without significant changes in serotonin or 5-HIAA levels. Ketanserin upregulated tryptophan hydroxylase 2 (TPH2) enzymatic activity.
Conclusions:
- Prolonged 5-HT2A receptor blockade with ketanserin did not ameliorate the adverse pro-depressive effects of fluoxetine in mice with abnormal 5-HT1A receptor functioning.
- Despite observed neurobiological changes, including reduced gene transcription and increased TPH2 activity, the combination therapy failed to produce therapeutic benefits in this model.
