Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with Abnormal 5-HT.sub.1A Receptor Functional Activity

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT.sub.1A receptors and upregulated 5-HT.sub.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.sub.2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT.sub.2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT.sub.1A and 5-HT.sub.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.sub.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.sub.2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT.sub.1A receptors.