Effects Of Fluoxetine Research Articles

4.26 The Effects of Fluoxetine and Sertraline on Height and Weight During Puberty

4.26 The Effects of Fluoxetine and Sertraline on Height and Weight During Puberty

Fluoxetine enhances the antitumor effect of olfactory ensheathing cell-thymidine kinase/ganciclovir gene therapy in human glioblastoma multiforme cells through upregulation of Connexin43 levels.

Glioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV-TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM-derived astrocytes and OECs-TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC-TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs-TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase-3 in the coculture of OECs-TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC-TK/GCV gene therapy on GBM cells.

Fluoxetine Promotes Longevity via Reactive Oxygen Species in Caenorhabditis elegans.

Although several antidepressants have been identified as potential geroprotectors, the effect and mechanism of fluoxetine, a representative selective serotonin reuptake inhibitor, on longevity have not been fully elucidated. Here, we found that fluoxetine promoted longevity in Caenorhabditis elegans with a concomitant extension of a healthy life span as indicated by increasing mobility, reducing fertility and lipofuscin accumulation, and enhanced resistance to different abiotic stresses. Fluoxetine increased the level of reactive oxygen species (ROS), and antioxidant N-acetylcysteine abolished ROS elevation and the pro-longevity effect of fluoxetine. Additionally, fluoxetine extended life span through the daf-2-sod-3 pathway in daf-16-dependent and -independent manners, and fluoxetine-induced life-span extension was abolished in C. elegans sod-3, daf-2, and daf-16 mutants. In conclusion, these findings suggest that fluoxetine can promote health and longevity in C. elegans via the interaction of ROS and insulin signaling.

Fluoxetine restrains allergic inflammation by targeting an FcɛRI-ATP positive feedback loop in mast cells.

There is a clinical need for new treatment options addressing allergic disease. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that have anti-inflammatory properties. We tested the effects of the SSRI fluoxetine on IgE-induced function of mast cells, which are critical effectors of allergic inflammation. We showed that fluoxetine treatment of murine or human mast cells reduced IgE-mediated degranulation, cytokine production, and inflammatory lipid secretion, as well as signaling mediated by the mast cell activator ATP. In a mouse model of systemic anaphylaxis, fluoxetine reduced hypothermia and cytokine production. Fluoxetine was also effective in a model of allergic airway inflammation, where it reduced bronchial responsiveness and inflammation. These data show that fluoxetine suppresses mast cell activation by impeding an FcɛRI-ATP positive feedback loop and support the potential repurposing of this SSRI for use in allergic disease.

Effect of Fluoxetine and Escitalopram on Heart Rate Variability (HRV) and Serum Potassium Level in Patients of Depression and Anxiety Disorders

Background The present study was conducted to generate data regarding the effect of fluoxetine as an anti-depressant and escitalopram as an antianxiety agent on heart rate variability (HRV). There is a scarcity of data regarding the correlation between selective serotonin reuptake inhibitors (SSRIs) and serum potassium levels. Purpose To find out the effect of SSRIs on HRV, and whether it is either dependent or independent of serum potassium level. Materials and Methods In this prospective, open-label, observational study, 70 participants were enrolled and divided into two groups, the fluoxetine group ( n = 35) and the escitalopram group ( n = 35) suffering from depression and anxiety, respectively. Parameters, like HRV, serum potassium level, heart rate, respiratory rate, and blood pressure, were measured baseline and after the first, second, and third months of treatment. HRV was calculated by root mean square deviation of successive differences between adjacent RR intervals (RMSSD). ECG (electrocardiogram) was recorded by Physio Pac Digital Polygraph software. All values were expressed as mean ± SD, and statistical analysis was done by using the repeated measure analysis of variance (ANOVA) test with Greenhouse–Geisser correction, post hoc analysis with Bonferroni correction, and SPSS 20.0 software. Results Among a total of 70 participants, post hoc tests using the Bonferroni correction showed a statistically significant difference between the HRV of the pretreatment group and after the second, and third month of fluoxetine therapy ( p < 0.05). In the escitalopram group, the Bonferroni correction showed a significant difference between the HRV of the pretreatment and third-month value ( p < 0.05). Repeated measure ANOVA with Greenhouse–Geisser correction showed no statistical significance of serum potassium at different time points ( p > 0.05). There were also no significant changes in heart rate, respiratory rate, and blood pressure at different points of time in both groups. Pearson’s correlation coefficient test for a relationship between HRV and serum potassium was negative at different time points. Conclusion Fluoxetine significantly increased HRV from the pretreatment value to the second and third months of treatment, whereas in the escitalopram group of participants, the third-month value of HRV was increased compared to the first month. The effect of SSRIs on HRV was independent of serum potassium levels at different time points suggesting that the effect of SSRIs on HRV was independent of serum potassium level.

Comparison of the efficacy of diltiazem versus fluoxetine in the treatment of distal esophageal spasm: A randomized-controlled-trial

Background and study aimDistal esophageal spasm is an uncommon esophageal motility disorder presenting with non-cardiac chest pain and dysphagia. The main goal of therapy is symptom relief with pharmacologic, endoscopic, and surgical therapies. Pharmacologic treatment is less invasive and is the preferred method of choice. The purpose of this study was to compare the effectiveness of diltiazem versus fluoxetine in the treatment of distal esophageal spasm. Patients and methodsA total of 125 patients with distal esophageal spasm diagnosed using endoscopy, barium esophagogram, and manometry were evaluated. Patients were divided into diltiazem and fluoxetine groups and received a 2-month trial of diltiazem + omeprazole or fluoxetine + omeprazole, respectively. Of 125 patients, 55 were lost to follow up and 70 were eligible for final analysis. Clinical signs and symptoms were assessed before and after therapy using four validated questionnaires: Eckardt score, short form-36, heartburn score, and the hospital anxiety and depression scale. ResultsBoth regimens significantly relieved symptoms (a decrease in mean Eckardt score of 2.57 and 3.18 for diltiazem and fluoxetine groups, respectively; and a decrease in mean heartburn score by 0.89 and 1.03 for diltiazem and fluoxetine groups, respectively). Patients’ quality of life improved based on short form-36 (an increase in mean score of 2.37 and 3.95 for fluoxetine and diltiazem groups, respectively). There was no relationship between patients’ improvement and severity of symptoms. Psychological findings based on the hospital anxiety and depression scale were inconsistent (a decrease in mean of 0.143 and 0.57 for fluoxetine and diltiazem groups, respectively; p > 0.05). ConclusionFluoxetine and diltiazem were effective for clinical symptom relief in patients with distal esophageal spasm, but were not promising for improving psychological symptoms. Neither regimen was superior in terms of efficacy. Consequently, it is key to consider side effects and comorbidities when choosing a therapy.

Metabolomic identification of biochemical changes induced by fluoxetine in an insulinoma cell line (MIN6).

The use of fluoxetine raises the risk of pancreatic beta-cell dysfunction. However, the specific mechanism behind its mechanism of action in beta cells is unknown. This study investigated the cellular response of MIN6 cells to fluoxetine using untargeted cell-based metabolomics. Metabolic profiling of MIN6 cells was performed using liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Sixty-six metabolites that had been differentially expressed between the control and fluoxetine-treated groups demonstrated that the citric acid cycle is mainly perturbed by fluoxetine treatment. The current study provides insights into the molecular mechanisms of fluoxetine effects in MIN6 cells.

Reproductive experience alters the effects of diazepam and fluoxetine on anxiety-like behaviour, fear extinction, and corticosterone levels in female rats

OverviewReproductive experience (pregnancy and motherhood) leads to long-term changes in the neurobiological and hormonal features of anxiety in rats and humans. The aim of this study was to examine whether reproductive experience alters the effects of two pharmacological treatments for anxiety, a benzodiazepine (diazepam) and a selective serotonin reuptake inhibitor (fluoxetine), on animal models of anxiety.MethodsIn Experiment 1, virgin (n = 47) and age-matched mother (n = 50) rats at 1-month post-weaning were injected with diazepam (1.3 mg/kg or 1.7 mg/kg, i.p.) or vehicle, in the proestrus (high estradiol/progesterone/allopregnanolone) or metestrus (low estradiol/progesterone/allopregnanolone) phase of the estrous cycle 30 min prior to the elevated plus maze (EPM). In Experiment 2, virgin (n = 25) and mother rats (n = 20) were administered fluoxetine (10 mg/kg) or vehicle for 2 weeks prior to being tested on a Pavlovian fear conditioning and extinction protocol, and the EPM.ResultsReplicating past research, in virgin rats, the low dose of diazepam produced anxiolytic-like effects in proestrus, but only the high dose was anxiolytic-like in metestrus. In contrast, in mother rats, both doses of diazepam were anxiolytic-like irrespective of estrous phase. Fluoxetine produced anxiogenic-like effects in virgin rats during fear extinction and the EPM, but had no behavioural effects in mothers. In contrast, fluoxetine increased plasma corticosterone levels measured 30-min post-EPM in mothers, but not virgin rats.ConclusionsReproductive experience alters the dose responsivity and efficacy of common anti-anxiety medications in female rats. These findings highlight the importance of considering reproductive status in studies on anxiety and its treatment.

16S rRNA gene sequencing reveals the effect of fluoxetine on gut microbiota in chronic unpredictable stress-induced depressive-like rats

ObjectivesGut microbiota is relevant to the pathogenesis of mental disorders including depression. This study aimed to investigate the influence of fluoxetine (FLX) on the gut microbiota in rats with Chronic Unpredictable Mild Stresses (CUMS)-induced depression.ResultsWe confirmed that the 28-day CUMS-induced depression rat model. Chronic FLX administration weakly improved depressive-like behaviors in rats. Illumina 16S rRNA gene sequencing on rat feces showed CUMS increased the relative abundance of Firmicutes (60.31% vs. 48.09% in Control, p < 0.05) and Lactobacillus genus (21.06% vs. 6.82% in control, p < 0.05); FLX and CUMS increased Bacilli class (20.00% ~ 24.08% vs. 10.31% in control, p < 0.05).ConclusionCollectively, our study showed that both CUMS and FLX changed the compositions of gut microbiota in rats. FLX and CUMS distinctly regulated the gut microbiota in depressed rats.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β-arrestin-2 (β-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the β-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the β-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

High-intensity interval training ameliorates chronic unpredictable mild stress-induced depressive behaviors via HDAC2-BDNF signaling in the ventral hippocampus

Major depressive disorder (MDD) is a devastating psychiatric disease, and current therapies could not well meet the demand for MDD treatment. Exercise benefits mental illness, and notably, exercise has been recommended as an alternative option for MDD treatment in some countries. However, the paradigm and intensity of exercise for MDD treatment has yet to be determined. High-intensity interval training (HIIT) is a potent and time-efficient type of exercise training and has gained popularity in recent years. In this study, we exposed the mice to chronic unpredictable mild stress (CUMS) and found HIIT exerted substantial antidepressant effect. Moreover, HIIT further enhanced the antidepressant effect of fluoxetine, a classic antidepressant in the clinic, confirming the antidepressant role of HIIT. HIIT significantly reversed the CUMS-induced upregulations in HDAC2 mRNA and protein level in the ventral hippocampus. We also found HIIT rescued the CUMS-induced downregulation in the expression of brain-derived neurotrophic factor (BDNF) and HDAC2 overexpression counteracted the HIIT-induced increase in BDNF level. More importantly, both virus-mediated HDAC2 overexpression and microinfusion of TrkB-Fc, a BDNF scavenger, in the ventral hippocampus abolished the antidepressant effect of HIIT. Together, our results strongly demonstrate that HIIT attenuates depressive behaviors, probably via HDAC2-BDNF signaling pathway and reveal that HIIT may serve as an alternative option for MDD treatment.

Acute Effects of Fluoxetine on Stress Responses and Feeding Motivation in Nile Tilapia

The selective serotonin reuptake inhibitor fluoxetine is one of the most commonly administered psychotropic medications; however, it has been recognized as toxic to aquatic life. In this study, we showed that stress responses and feeding motivation in Nile tilapia were affected by acute exposure to fluoxetine. To reach that conclusion, we exposed Nile tilapia to 0, 1 or 10 µg/L (environmentally/biologically relevant doses) of fluoxetine over a 24 h period and then exposed them to a handling stressor. We found that the 10 µg/L dose enhanced cortisol response to stress but caused an earlier decrease in the ventilation boost induced by that stressor. An immediate ventilation boost after stressful stimuli indicates sympathetic activation. Thus, this suggests that fluoxetine decreased sympathetic nervous system activity but augmented hypothalamus–pituitary–interrenal axis activity in the fish. Both feeding latency and ingestion were similar among the tested conditions; however, a multiple logistic regression model revealed that in the presence of a stressor or fluoxetine, the Nile tilapia tended to ingest less food but there was a higher probability of this decrease to be associated with fluoxetine. We concluded that acute exposure to environmentally/biologically relevant fluoxetine concentrations over 24 h acted as a modifying factor for Nile tilapia stress physiology and tended to interfere with feeding motivation. An acute stress response is an emergency reaction that contributes to the recovery of homeostasis. In the presence of fluoxetine, modifications of acute stress responses and the tendency to reduce food intake, which restricts the ability to replace the energy spent on stress responses, could compromise the resumption of homeostasis and an animal’s adjustment to different environmental contexts, such as those associated with aquaculture, in which anthropogenic stressors inevitably occur.

Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling – a potential therapeutic concept?

BackgroundMajor depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.ObjectivesThe purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.MethodsThe effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.ResultsThe results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, aremediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.ConclusionsTrk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.

Isoalantolactone relieves depression-like behaviors in mice after chronic social defeat stress via the gut-brain axis

RationaleThe management of depression continues to be challenging despite the variety of available antidepressants. Herbal medicines are used in many cultures but lack stringent testing to understand their efficacy and mechanism of action. Isoalantolactone (LAT) from Elecampane (Inula helenium) improved the chronic social defeat stress (CSDS)-induced anhedonia-like phenotype in mice comparable to fluoxetine, a selective serotonin reuptake inhibitor (SSRI).ObjectivesCompare the effects of LAT and fluoxetine on depression-like behaviors in mice exposed to CSDS.ResultThe CSDS-induced decrease in protein expression of postsynaptic density (PSD95), brain derived neurotrophic factor (BDNF), and glutamate receptor subunit-1 (GluA1) in the prefrontal cortex was restored by LAT. LAT showed robust anti-inflammatory activity and can lessen the increase in IL-6 and TNF-α caused by CSDS. CSDS altered the gut microbiota at the taxonomic level, resulting in significant changes in α- and β-diversity. LAT treatment reestablished the bacterial abundance and diversity and increased the production of butyric acid in the gut that was inhibited by CSDS. The levels of butyric acid were negatively correlated with the abundance of Bacteroidetes, and positively correlated with those of Proteobacteria and Firmicutes across all treatment groups.ConclusionsThe current data suggest that, similar to fluoxetine, LAT show antidepressant-like effects in mice exposed to CSDS through the modulation of the gut-brain axis.

Study the effects of empagliflozin on model of chronic depression and interleukin-6 in the brain of male rats

Abstract Background: Empagliflozin (EMP) is an oral anti-diabetic drug with pleiotropic effects such as anti-inflammatory properties. Objectives: To evaluate the antidepressant effect of EMP and describe the link between stress and interleukin-6 (IL-6) level in the brains of male rats. Materials and Methods: In this experiment, 50 rats were separated into five groups G1–G5. The sucrose preference test (SPT) was used to examine the antidepressant effects of fluoxetine and EMP. Rat interleukin enzyme-linked immunosorbent assay kit was used to measure the IL-6 level in rat brain tissue. SPT was performed on each rat on days 0, 10, and 25. Chronic unpredictable stress (CUS) was performed on each rat for 24 days. Results: By the end of day 10, all rats subjected to the CUS program had a substantial (P &lt; 0.05) reduction in sucrose intake index compared to day 0. EMP significantly increases sucrose intake compared to the stressed group. In comparison to the CUS group, fluoxetine significantly increases sucrose intake (P &lt; 0.05). In terms of IL-6, the mean IL-6 level in G2 was considerably greater than in G1. When compared to group 2, the mean IL-6 level was considerably lower in G3 and G5. Conclusions: EMP has antidepressant-like effects and can counteract the impact of stress-increased IL-6 levels in the brains of depressed rats.

Comparison of the effects of amitriptyline, melipramine and fluoxetine on acquisition and spatial alteration of avoidance responses in rats

The effects of amitriptyline (10 mg/kg), melipramine (10 mg/kg), and fluoxetine (5 mg/kg) on the acquisition of conditioned active avoidance responses and their spatial alteration in rats were studied. During the acquisition of avoidance, a passage in the partition was open, adjacent to the rear wall of the shuttle chamber. On the 5th experimental day after the end of the training, this distal opening was closed and the proximal one was opened, after which avoidance performance under changed conditions was tested for 20 trials. Melipramine and amitriptyline accelerated the acquisition of avoidance responses. Changing the location of the opening disrupted the learned skill, especially in the control animals. Melipramine and fluoxetine statistically significantly (in contrast to amitriptyline) accelerated the recovery of the level of avoidance. The positive effect of melipramine and fluoxetine is explained by a psychostimulating component in their spectrum. The inability of amitriptyline to produce a significant effect in this model is due to its psychosedative properties. The data obtained allow us to conclude that the acquisition of the active conditioned avoidance responses and their spatial modification can be used to analyze the antidepressant activity of pharmacological agents.

Metabolic Fingerprints of Effective Fluoxetine Treatment in the Prefrontal Cortex of Chronically Socially Isolated Rats: Marker Candidates and Predictive Metabolites.

The increasing prevalence of depression requires more effective therapy and the understanding of antidepressants' mode of action. We carried out untargeted metabolomics of the prefrontal cortex of rats exposed to chronic social isolation (CSIS), a rat model of depression, and/or fluoxetine treatment using liquid chromatography-high resolution mass spectrometry. The behavioral phenotype was assessed by the forced swim test. To analyze the metabolomics data, we employed univariate and multivariate analysis and biomarker capacity assessment using the receiver operating characteristic (ROC) curve. We also identified the most predictive biomarkers using a support vector machine with linear kernel (SVM-LK). Upregulated myo-inositol following CSIS may represent a potential marker of depressive phenotype. Effective fluoxetine treatment reversed depressive-like behavior and increased sedoheptulose 7-phosphate, hypotaurine, and acetyl-L-carnitine contents, which were identified as marker candidates for fluoxetine efficacy. ROC analysis revealed 4 significant marker candidates for CSIS group discrimination, and 10 for fluoxetine efficacy. SVM-LK with accuracies of 61.50% or 93.30% identified a panel of 7 or 25 predictive metabolites for depressive-like behavior or fluoxetine effectiveness, respectively. Overall, metabolic fingerprints combined with the ROC curve and SVM-LK may represent a new approach to identifying marker candidates or predictive metabolites for ongoing disease or disease risk and treatment outcome.

Stimulatory effect of fluoxetine and desipramine, but not mirtazapine on C26 colon carcinoma hepatic metastases formation: association with cytokines.

Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such medications in the development of metastasis is unclear. In this study, we investigated the effects of fluoxetine, desipramine, and mirtazapine on the liver metastasis of murine C26 colon carcinoma (cc). Balb/c male mice were administered these antidepressants intraperitoneally (i.p.) for 14 days following intrasplenic injections of C26 colon carcinoma cells. Desipramine and fluoxetine, but not mirtazapine, significantly increased the number of tumor foci and total volume of the tumor in liver tissue. This effect was associated with a decrease in the ability of splenocytes to produce interleukin (IL)-1β and interferon (IFN)-γ and an increase in their ability to produce interleukin (IL)-10. Similar changes were observed in plasma IL-1β, IFN-γ, and IL-10 levels. The current study demonstrates that the stimulatory effect of desipramine and fluoxetine, but not mirtazapine, on experimental colon cancer liver metastasis is associated with a suppression of immune defenses against the tumor.

Vagus nerve-dependent effects of fluoxetine on anxiety- and depression-like behaviors in mice

The vagus nerve is a major pathway in the body that is responsible for regulating the activity of the parasympathetic nervous system, which plays an important role in mood disorders including anxiety and depression. Fluoxetine, also known as Prozac, is widely used to treat depression. Nevertheless, there are few studies on the vagus nerve-mediated action of fluoxetine. In this study, we aimed to investigate the vagus nerve-dependent actions of fluoxetine in mice with restraint stress-induced or antibiotics-induced anxiety- and depression-like behaviors. Compared to sham operation, vagotomy alone did not exhibit significant effects on behavioral changes and serotonin-related biomarkers in mice not exposed to stress, antibiotics, or fluoxetine. Oral administration of fluoxetine significantly alleviated anxiety- and depression-like behaviors. However, celiac vagotomy significantly attenuated the anti-depressive effects of fluoxetine. The vagotomy also inhibited the effect of fluoxetine to attenuate restraint stress- or cefaclor-induced reduction in serotonin levels and Htr1a mRNA expression in the hippocampus. These findings suggest that the vagus nerve may regulate the efficacy of fluoxetine for depression.

Effects of chronic combined treatment with ketanserin and fluoxetine in B6.CBA-D13Mit76C recombinant mice with abnormal 5-НТ&lt;sub&gt;1a&lt;/sub&gt; receptor functional activity

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by altered sensitivity of 5-HT1A receptors and greater Htr1a gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced 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. Fluoxetine, ketanserin, and fluoxetine + ketanserin decreased functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. Additionally, all the tested drug regimens decreased 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 during abnormal functioning of 5-HT1A receptors.