Administration Of Fluoxetine Research Articles

Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine's inhibitory effects on necroptotic kinases.

The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (CUMS) mouse model and a corticosterone (Cort)-induced human astrocyte injury model in vitro, we found that mice treated with chronic unpredictable mild stress for 3-5weeks presented depressive-like behaviors and reduced body weight gain, accompanied by a reduction in astrocytes and a decrease in astrocytic brain-derived neurotropic factors (BDNF), by activation of necroptotic kinases, including RIPK1 (receptor-interacting protein kinase 1)/p-RIPK1, RIPK3 (receptor-interacting protein kinase 3)/p-RIPK3 and MLKL (mixed lineage kinase domain-like protein)/p-MLKL, and by upregulation of inflammatory cytokines in astrocytes of the mouse hippocampus. In contrast, necroptotic kinase inhibitors suppressed Cort-induced necroptotic kinase activation, reduced astrocytes, astrocytic necroptosis and dysfunction, and decreased Cort-mediated inflammatory cytokines in astrocytes. Treatment with fluoxetine (FLX) for 5weeks improved chronic unpredictable mild stress-induced mouse depressive-like behaviors; simultaneously, fluoxetine inhibited depression-induced necroptotic kinase activation, reversed the reduction in astrocytes and astrocytic necroptosis and dysfunction, decreased inflammatory cytokines and upregulated brain-derived neurotropic factors and 5-HT1A levels. Furthermore, fluoxetine had no direct inhibitory effect on receptor-interacting protein kinase 1 phosphorylation. The combined administration of fluoxetine and necroptotic kinase inhibitors further reduced corticosterone-induced astrocyte injury. In conclusion, the reduction in astrocytes caused by depressive-like models in vivo and in vitro may be associated with the activation of necroptotic kinases and astrocytic necroptosis, and fluoxetine exerts an antidepressive effect by indirectly inhibiting receptor-interacting protein kinase 1-mediated astrocytic necroptosis.

The influence of fluoxetine on orthodontic tooth movement in rats.

This study aimed to evaluate the effects of chronic use of fluoxetine on the amount of orthodontic tooth movement and tissue changes in rats. A total of 192 Wistar rats were divided into 4 groups: S, 0.9% saline solution; F, 20 mg/kg of fluoxetine; SM, 0.9% saline solution with orthodontic movement; and FM, 20 mg/kg of fluoxetine with orthodontic movement. After 30 days of daily saline or fluoxetine administration, an orthodontic device (25cN) was used to mesially displace the first molar in animals of the groups SM and FM. The animals were euthanized 2, 7, 14, and 28 days after placement of the orthodontic appliances and animals of groups S and F were euthanized at the same time. The assessment of tooth movement was made in gypsum castings, the collagen neoformation was assessed by polarization microscopy, the number of osteoclasts and root resorption were evaluated using tartrate-resistant acid phosphatase, and presence of hyalinized areas was assessed by hematoxylin-eosin staining. Fluoxetine did not affect the amount of tooth displacement, percentage of collagen, number of osteoclasts, and presence of hyalinized areas (P>0.05). There was a higher frequency of root resorption areas in the FM group than in the SM group only on the second day (P<0.05). The findings of this study show that chronic use of 20 mg/kg fluoxetine does not affect the amount of tooth movement, collagen neoformation, number of osteoclasts, or hyalinized areas and does not affect root resorption until the last day of orthodontic movement.

Fluoxetine treatment during the postpartal period may have short-term impacts on murine maternal skeletal physiology.

Postpartum depression affects many individuals after parturition, and selective serotonin reuptake inhibitors (SSRIs) are often used as the first-line treatment; however, both SSRIs and lactation are independently associated with bone loss due to the role of serotonin in bone remodeling. Previously, we have established that administration of the SSRI fluoxetine during the peripartal period results in alterations in long-term skeletal characteristics. In the present study, we treated mice with either a low or high dose of fluoxetine during lactation to determine the consequences of the perturbation of serotonin signaling during this time period on the dam skeleton. We found that lactational fluoxetine exposure affected both cortical and trabecular parameters, altered gene expression and circulating markers of bone turnover, and affected mammary gland characteristics, and that these effects were more pronounced in the dams that were exposed to the low dose of fluoxetine in comparison to the high dose. Fluoxetine treatment during the postpartum period in rodents had short term effects on bone that were largely resolved 3 months post-weaning. Despite the overall lack of long-term insult to bone, the alterations in serotonin-driven lactational bone remodeling raises the question of whether fluoxetine is a safe option for the treatment of postpartum depression.

NEUROPROTECTIVE AND ANTIOXIDANT ACTIVITIES OF AQUEOUS EXTRACT MORINGA OLEIFERA LEAVES

Objective: To investigate the neuroprotective and antioxidant effects of leaves aqueous extract Moringa oleifera (MW) in chronic stress mouse models.&#x0D; Methods: Water immersion and stress restraint for 16 d to obtain a chronic stress model animal. Moringa extract flour dissolved in Aquades, dose 800 mg/kg for 23 d, for chronic Stress+MOW group. Fluoxetine in aquades at a dose of 18 mg/kg BW for 23 d for chronic stress group+Fluoxetine. Aquades were given to normal mice (group N), and mice under chronic stress conditions (chronic stress control group). Furthermore, measure behavioral abnormalities by testing depressive behavior and oxidative stress parameters such as anxiety, Brain-derived neurotrophic factors (BDNF).&#x0D; Results: Moringa oleifera water extract administration can improve behavioral disorders caused by stress by decreasing immobility time on the Force swim test, increasing time in the middle area, and increasing the number of returns to center areas on the Open field test. When chronically stressed mice were given fluoxetine and MOW, their MDA levels (p=0.008 and 0.041, respectively) and SOD activity (p=0.001 and 0.004) decreased significantly compared to the chronic stress control group. In contrast, Catalase activity increased significantly in chronically stressed mice given fluoxetine and MOW compared to the chronic stress control group (p=0.010 and 0.013). Administration of fluoxetine and MOW may increase the expression of mRNA BDNF compared to the chronic stress control group (p=0.000 and 0.013).&#x0D; Conclusion: The study found that MOW can improve behavioral abnormalities, namely anxiety and depression behavior caused by chronic stress exposure, through antioxidant pathways and oxidant systems, and also BDNF

Inhibitory effects of fluoxetine on the secretion of inflammatory mediators and JAK/STAT3 and JNK/TLR4 gene expression.

Selective serotonin reuptake inhibitors (SSRIs) are the most common class of medicines used for the treatment of major depression. Recent studies have reported an association between depression and inflammation and suggested the significant effects of SSRIs on inflammatory processes. The current study aimed to evaluate the effects of fluoxetine, an SSRI, on the level of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in the rat serum and RAW264.7 mouse macrophage cell line, using ELISA sandwich assays. Also, the expression of inflammatory genes, including JAK/STAT3 and TLR4/JNK, was examined in macrophages, using real-time quantitative reverse transcription PCR to determine the potential mechanism of fluoxetine in inflammation. The rats received fluoxetine (10, 20, and 40mg/kg) 30min before lipopolysaccharide (LPS) treatment for 90min. The cells received different doses of fluoxetine (5, 10, and 20µg/mL) before stimulation with LPS for 24 or 48h. The serum concentrations of IL-1β, IL-6, and TNF-α were reduced in rats and cells treated with fluoxetine. Following fluoxetine administration, the expression of JAK/STAT3 and TLR4/JNK genes was significantly decreased in the RAW264.7 cells treated with LPS for 24h. However, after 48h of treatment with LPS, fluoxetine failed to diminish the elevated expression of JAK and JNK genes, while it significantly decreased the expression of STAT3 and TLR4 genes. The findings revealed that fluoxetine has anti-inflammatory properties, mainly due to the reduction of inflammatory cytokines and inhibition of JAK/STAT3 and TLR4/JNK gene expression in macrophages.

Fluoxetine increased adult neurogenesis is mediated by 5-HT3 receptor

Adult neurogenesis is an aspect of structural plasticity that remains active during adulthood in some brain regions. One of them is the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. Adult neurogenesis is reduced by different factors and in disorders of the CNS, including major depression. Antidepressant treatments, such as chronic fluoxetine administration, recover the normal level of adult neurogenesis. Fluoxetine treatment increases the free concentration of the neurotransmitter serotonin and this monoamine is implicated in the regulation of the neurogenic process; however, the target of the action of this neurotransmitter has not been fully elucidated. In this study, we have tried to determine the relevance of the serotonin receptor 3 (5-HT3) in the hippocampal neurogenesis of adult rats. We have used fluorescent immunohistochemistry to study the expression of the 5-HT3 receptor in different neurogenesis stages in the SGZ, identifying its expression in stem cells, amplifying neural progenitors and immature neurons. Moreover, we have studied the impact of a 5-HT3 antagonist (ondansetron) in the fluoxetine-induced adult neurogenesis. We observed that fluoxetine alone increases the number of both proliferating cells (ki67 positive) and immature neurons (DCX positive) in the SGZ. By contrast, co-treatment with ondansetron blocked the increase in proliferation and neurogenesis. This study demonstrates that the activation of 5-HT3 receptors is necessary for the increase of adult neurogenesis induced by fluoxetine.

Preferential Modulatory Action of 5-HT2A Receptors on the Dynamic Regulation of Basal Ganglia Circuits.

In rodents, cortical information is transferred to the substantia nigra pars reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG) circuits implicated in motor and cognitive/motivational behaviors, respectively. The serotonergic 5-HT2A receptors are located in both of these neuronal networks, displaying topographical differences with a high expression in the associative/limbic territories, and a very low expression in the subthalamic nucleus. This study investigated whether the stimulation of 5-HT2A receptors could have a specific signature on the dynamic regulation of BG circuits, preferentially modulating the mPF information processing through trans-striatal pathways. We performed in vivo single-unit extracellular recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous and cortically evoked activity of lateral and medial SNr neurons in male rats (involved in motor and mPF circuits, respectively). TCB-2 (50-200 µg/kg, i.v.) increased the basal firing rate and enhanced the cortically evoked inhibitory response of medial SNr neurons (transmission through the direct striato-nigral pathway). A prior administration of the preferential 5-HT2A receptor antagonist MDL11939 (200 µg/kg, i.v.) did not modify any electrophysiological parameter, but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis inhibitor pCPA (4-chloro-dl-phenylalanine methyl ester hydrochloride), TCB-2 failed to induce the above-mentioned effects, thus suggesting the contribution of endogenous 5-HT. However, the mobilization of 5-HT induced by the acute administration of fluoxetine (10 mg/kg, i.p.) did not mimic the effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors have a preferential modulatory action on the dynamic regulation of BG circuitry.SIGNIFICANCE STATEMENT Motor and medial prefrontal (mPF) basal ganglia (BG) circuits play an important role in integrative brain functions like movement control or cognitive/motivational behavior, respectively. Although these neuronal networks express 5-HT2A receptors, the expression is higher in associative/limbic structures than in the motor ones. We show a topographical-dependent dissociation in the effects triggered by the 5HT2A agonist TCB-2, which specifically increases the medial substantia nigra pars reticulata neuron activity and has a preferential action on mPF information processing through the striato-nigral direct pathway. These are very likely to be 5-HT2A receptor-mediated effects that require mobilization of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT2A receptors on the dynamic regulation of BG circuits.

Mechanism of lily bulb and Rehmannia decoction in the treatment of lipopolysaccharide-induced depression-like rats based on metabolomics study and network pharmacology

Context Lily bulb and Rehmannia decoction (LBRD), consisting of Lilium henryi Baker (Liliaceae) and Rehmannia glutinosa (Gaertn) DC (Plantaginaceae), is a specialized traditional Chinese medicine formula for treating depression. However, the underlying mechanisms, especially the relationship between LBRD efficacy and metabolomics, remains unclear. Objective This study was aimed to investigate the metabolic mechanism of LBRD in treating depression. Materials and methods Network pharmacology was conducted using SwissTargetPrediction, DisGeNET, DrugBank, Metascape, etc., to construct component-target-pathway networks. The depression-like model was induced by intraperitoneal injection with lipopolysaccharide (LPS) (0.3 mg/kg) for 14 consecutive days. After the administration of LBRD (90 g/kg) and fluoxetine (2 mg/kg) for 14 days, we assessed behaviour and the levels of neurotransmitter, inflammatory cytokine and circulating stress hormone. Prefrontal metabolites of rats were detected by using liquid chromatography–mass spectrometry metabolomics method. Results The results of network pharmacology showed that LBRD mainly acted on neurotransmitter and second messenger pathways. Compared to the model group, LBRD significantly ameliorated depressive phenotypes and increased the level of 5-HT (13.4%) and GABA (24.8%), as well as decreased IL-1β (30.7%), IL-6 (32.8%) and TNF-α (26.6%). Followed by LBRD treatment, the main metabolites in prefrontal tissue were contributed to retrograde endocannabinoid signalling, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, autophagy signal pathway, etc. Discussion and conclusions LBRD were effective at increasing neurotransmitter, attenuating proinflammatory cytokine and regulating glycerophospholipid metabolism and glutamatergic synapse, thereby ameliorating depressive phenotypes. This research will offer reference for elucidating the metabolomic mechanism underlying novel antidepressant agents contained LBRD formula.

Effect of Fluoxetine and Acacetin on Central Vestibular Compensation in an Animal Model of Unilateral Peripheral Vestibulopathy.

Damage to the peripheral vestibular system is known to generate a syndrome characterized by postural, locomotor, oculomotor, perceptual and cognitive deficits. Current pharmacological therapeutic solutions for these pathologies lack specificity and efficacy. Recently, we demonstrated that apamin, a specific SK channel blocker, significantly reduced posturo-locomotor and oculomotor deficits in the cat and the rat. The aim of the present study was to test the antivertigo potential of compounds belonging to the SK antagonists family, such as Acacetin and Fluoxetine. Young rats were subjected to unilateral ototoxic lesions of the vestibular organ using transtympanic administration of arsanilic acid (TTA) to evoke unilateral vestibular loss (UVL). Vestibular syndrome was monitored using behavioural evaluation allowing appreciation of the evolution of static and dynamic posturo-locomotor deficits. A significant effect of the TTA insult was only found on the distance moved, the mean body velocity and the not moving time. From day 2 to week 2 after TTA, the distance moved and the mean body velocity were significantly decreased, while the not moving time was significantly increased. Acacetin does not evoke any significant change in the vestibular posturo-locomotor parameters’ kinetics. Administration of Fluoxetine two weeks before TTA and over three weeks after TTA (preventive group) does not evoke any significant change in the vestibular posturo-locomotor parameters’ kinetics. Administration of Fluoxetine from three weeks after TTA significantly delayed the functional recovery. This study demonstrates that Acacetin or Fluoxetine in TTA vestibulo-injured rats does not bring any significant benefit on the posture and locomotor balance deficits.

Ameliorating effect of fluoxetine on tamoxifen-induced memory loss: The role of corticolimbic NMDA receptors and CREB/BDNF/cFos signaling pathways in rats

Tamoxifen-induced cognitive dysfunction may lead to fluoxetine consumption in patients with breast cancer. Since the brain mechanisms are unclear in tamoxifen/fluoxetine therapy, the blockade effect of hippocampal/amygdala/prefrontal cortical NMDA receptors was examined in fluoxetine/tamoxifen-induced memory retrieval. We also assessed the corticolimbic signaling pathways in memory retrieval under the drug treatment in adult male Wistar rats. Using the Western blot technique, the expression levels of the cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and cFos were evaluated in the corticolimbic regions. The results showed that pre-test administration of fluoxetine (3 and 5 mg/kg, i.p.) improved tamoxifen-induced memory impairment in the passive avoidance learning task. Pre-test bilateral microinjection of D-AP5, a selective NMDA receptor antagonist, into the dorsal hippocampal CA1 regions and the central amygdala (CeA), but not the medial prefrontal cortex (mPFC), inhibited the improving effect of fluoxetine on tamoxifen response. It is important to note that the microinjection of D-AP5 into the different sites by itself did not affect memory retrieval. Memory retrieval increased the signaling pathway of pCREB/CREB/BDNF/cFos in the corticolimbic regions. Tamoxifen-induced memory impairment decreased the hippocampal/PFC BDNF level and the amygdala level of pCREB/CREB/cFos. The improving effect of fluoxetine on tamoxifen significantly increased the hippocampal/PFC expression levels of BDNF, the PFC/amygdala expression levels of cFos, and the ratio of pCREB/CREB in all targeted areas. Thus, NMDA receptors’ activity in the different corticolimbic regions mediates fluoxetine/tamoxifen memory retrieval. The corticolimbic synaptic plasticity changes likely accompany the improving effect of fluoxetine on tamoxifen response.

Promiscuous or Dirty drug with Multifunctional Druggability nature of Curcumin (Curcuma longa Linn.); Repurposing in propranolol withdrawal-induced OCD related Anxiety: A promising drug discovery besides One-Drug-One-Receptor approach via in silico in vivo studies

Background: Curcumin (Curcuma longa) and propranolol display a plethora of pharmacological activity linked with multifunctional druggable nature designated as a promiscuous or dirty drug (magic shotguns) that hit 'on-target as well as 'off-target' (anti-target). Multifactorial origins, with complex neuronal networks and broad-spectrum symptomatology, operates most CNS disorders. Anxiety is one of the comorbidities in the psychogenic spectrum of obsessive-compulsive disorder (OCD). The present study of OCD has been based on its multifunctionality and diverse drug potential, tailoring together the morbidity and comorbidity patterns of OCD. Very few multimodal drugs did trial in this regard, which has multifunctional druggability, except selective serotonin reuptake inhibitors (SSRIs) that work via the one-drug-one-receptor-one-disease approach; however, with inter-individual variability, unwanted side effects and limited multifunctionality with the druggable targets. SSRI success rates in OCD and its related disorder are minimal, especially in the adversity of comorbidity pattern. Objective: The principal objective of the current research was to testify the multifunctional druggable plethora of curcumin via repurposing of its dirty drug nature to reverse the obsessed anxiety of propranolol withdrawal-induce mice, besides the "one drug one receptor" approach or magic bullet. Methods: The present study evaluated OCD related anxiety-like behavior after different periods of abstinence (24 h, 7 and 21 days) from repeated propranolol (10 mg/kg) administration in mice. In addition, we also examined the action of curcumin (EERCL-50 mg/kg) and fluoxetine (20 mg/kg) for the attenuation or reversal of OCD related anxiety-like behavior after seven days to 24 hours propranolol withdrawal. The initial stage of the hypothesis toward the target of curcumin was identified via in-silico using SwissADME drug-likeness study, followed by in-vivo studies using Swiss albino mice. Evaluation for the same did use elevated plus maze (EPM), marble-burying behaviour (MBB) and motor activity (MA) test as a model. Further, did also investigate the antioxidant activity. Result: The result revealed a decrease in all parameters 24 hours and 14 days after exposure to propranolol, indicating anxious behaviour. The administration of curcumin and fluoxetine after 24 hrs of abstinence reduced animal anxiety in EPM; after the abstinence periods, the drug reduced the MA in the MBB. Curcumin reversed the anxiogenic effect induced by propranolol in EPM. The value of p&lt;0.05 was considered statistically significant. Conclusion: Results revealed that propranolol might, to a large extent, impart to withdrawal-induced obsessed anxiety, and curcumin could effectively treat propranolol dependent obsessed mice. Further, curcumin anti-compulsive competency substantially showed promising success besides one drug-one receptor-one disease approach or magic bullet.

The selective serotonin reuptake inhibitor fluoxetine has direct effects on beta cells, promoting insulin secretion and increasing beta-cell mass.

AimThis study investigated whether therapeutically relevant concentrations of fluoxetine, which have been shown to reduce plasma glucose and glycated haemoglobin independent of changes in food intake and body weight, regulate beta‐cell function and improve glucose homeostasis.MethodsCell viability, insulin secretion, beta‐cell proliferation and apoptosis were assessed after exposure of MIN6 beta cells or isolated mouse and human islets to 0.1, 1 or 10 μmol/L fluoxetine. The effect of fluoxetine (10 mg/kg body weight) administration on glucose homeostasis and islet function was also examined in ob/ob mice.ResultsExposure of MIN6 cells and mouse islets to 0.1 and 1 μmol/L fluoxetine for 72 hours did not compromise cell viability but 10 μmol/L fluoxetine significantly increased Trypan blue uptake. The dose of 1 μmol/L fluoxetine significantly increased beta‐cell proliferation and protected islet cells from cytokine‐induced apoptosis. In addition, 1 μmol/L fluoxetine induced rapid and reversible potentiation of glucose‐stimulated insulin secretion from islets isolated from mice, and from lean and obese human donors. Finally, intraperitoneal administration of fluoxetine to ob/ob mice over 14 days improved glucose tolerance and resulted in significant increases in beta‐cell proliferation and enhanced insulin secretory capacity.ConclusionsThese data are consistent with a role for fluoxetine in regulating glucose homeostasis through direct effects on beta cells. Fluoxetine thus demonstrates promise as a preferential antidepressant for patients with concomitant occurrence of depression and diabetes.

Centella asiatica L. Urban protects against morphological aberrations induced by chronic unpredictable mild stress in rat’s hippocampus via attenuation of oxidative stress

ABSTRACT Thepresent study evaluated the effect of Centellaasiatica L. Urban (CA) extracts on ultrastructure and oxidative stressparameters on chronic unpredictable mild stress (CUMS) rat’s hippocampi. Ratswere divided into six groups (n=6) and treated as follows: Group 1, Unstressed+ normal saline (control); Group 2, CUMS + normal saline (Model); Group 3, CUMS+ Flx (10 mg/kg) (FLX); Groups 4, CUMS + CA (200 mg/kg) (CA 200); Group 5, CUMS+ CA (400 mg/kg) (CA 400) and Group 6, CUMS + CA (800 mg/kg) (CA 800). Ninedifferent stressors were administered to the rats for 8 weeks consecutively,with concurrent administration of fluoxetine or CA. The hippocampi of the ratswere evaluated by transmission electron microscopy (TEM) and oxidative stress biomarkerswere also determined. Qualitative TEM results showed defective mitochondria,nucleus, myelin sheaths and reduced numbers of synapses in CUMS rats as well asincreased oxidative stress biomarkers. Administration of CA prevented some ofthe structural and biochemical aberrations observed in response to stress in amanner comparable with fluoxetine, a selective serotonin-reuptake inhibitor. Conclusively,CA ameliorates structural defects induced by CUMS in the rat hippocampus, witha potential therapeutic importance in the treatment of stress and depression.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice

NAD+—dependent histone deacetylases (sirtuins 1–7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

Inhibitory effects of fluoxetine and duloxetine on the pharmacokinetics of metoprolol in vivo and in vitro.

Depression is common among people with cardiovascular diseases. Therefore, the combined use of antidepressants and cardiovascular drugs is very common, which increases the possibility of drug interaction. Simultaneously compare the effects of duloxetine and fluoxetine on metoprolol metabolism, and provide evidence-based guidance for medication safety. Sprague-Dawley rats were randomly divided into three groups: group A (10.3mg/kg metoprolol alone), group B (10.3mg/kg metoprolol + 6.2mg/kg fluoxetine), and group C (10.3mg/kg metoprolol + 6.2mg/kg duloxetine). Tail vein blood was collected and subjected to the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) detection. Moreover, in vitro inhibition of fluoxetine and duloxetine were assessed by incubating liver microsomes and CYP2D6.1 with metoprolol. In in vivo study, the administration of fluoxetine or duloxetine significantly increased the AUC(0-𝑡) and AUC(0-∞) of metoprolol (P < 0.05). Differences between fluoxetine and duloxetine in plasma concentration were also investigated, and their pharmacokinetic parameters such as AUC(0-𝑡) and AUC(0-∞) were significantly distinct (P < 0.05). In vitro, fluoxetine and duloxetine inhibited the metabolism of metoprolol via mixed competitive mechanism of cytochrome P450. IC50 values of fluoxetine and duloxetine were 12.86 and 2.51 μM, respectively. Moreover, the metabolism rate of metoprolol was inhibited to 19.62% and 17.14% in recombinant human CYP2D6.1 by fluoxetine and duloxetine, respectively. Duloxetine showed a more significant inhibitory potential compared to fluoxetine in vitro, but the main pharmacokinetic parameters of fluoxetine and duloxetine revealed differences in inhibiting metoprolol metabolism in vivo.

Fluoxetine exposure throughout neurodevelopment differentially influences basilar dendritic morphology in the motor and prefrontal cortices

The significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions.

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

Attention deficit hyperactivity disorder (ADHD) affects children and adults, and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. Psychostimulants, which are the primary treatment for ADHD, target monoamine transporters and have a paradoxical calming effect, but their mechanism of action is unclear. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the actions on serotonin neurotransmission. On the other hand, newer non‐stimulant class of drugs such as atomoxetine and guanfacine suggest that targeting the norepinephrine (NE) system in the PFC might explain this paradoxical calming effect. We sought to decipher the mechanism of this paradoxical effect of psychostimulants through an integrated approach using ex vivo monoamine efflux experiments, monoamine transporter knockout mice, drug infusions and behavior. Our ex vivo efflux experiments reveal that NE transporter (NET) blocker desipramine elevates both norepinephrine and dopamine but not serotonin levels, in PFC tissue slices from wild‐type and DAT‐KO but not NET‐KO mice. However, serotonin (5‐HT) transporter (SERT) inhibitor fluoxetine elevates only serotonin in all three genotypes. Systemic administration of both desipramine and fluoxetine but local PFC infusion of only desipramine and not fluoxetine inhibits hyperactivity in the DAT‐KO mice. In contrast, pharmacological norepinephrine depletion but dopamine elevation using Nepicastat also inhibits hyperactivity in DAT‐KO mice. Together, these data suggest that elevation of PFC dopamine and not norepinephrine or serotonin as a convergent mechanism for the paradoxical psychostimulant effects observed in ADHD therapy.

A 10‐Year Nationwide Pharmacovigilance Assessment on Anti‐Obesity Medications and Factors Associated with Serious Adverse Events

Study ObjectiveTo compare the adverse events (AEs) profiles of medications prescribed to treat obesity and identify factors associated with serious adverse events (SAEs) by utilizing nationwide spontaneous AE reporting database in Korea.HypothesisThe AE profiles may differ by anti‐obesity agents and patient‐specific factors may aggravate the risk of SAEs.MethodsRetrospective analysis was performed on ADE records spontaneously reported from January 2010 to December 2019 to the Korean Adverse Event Reporting System (KAERS) constructed by Korea Institute of Drug Safety and Risk Management. This analysis included 10 anti‐obesity agents prescribed for overweight, obesity (ICD‐10 code E66) and abnormal weight gain (ICD10 Code E63.5). All AEs were grouped using preferred terms and System Oran Classes (SOC) per the WHO‐Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with SAEs identified based on International Conference on Harmonization E2D Guidelines, and the odds ratio (OR) was reported with 95% confidence intervals (CIs). Any p‐values &lt;0.05 was considered statistically significant. All statistical analyses were performed with SPSS 25.0 (Version 25.0; IBM SPSS Statistics for Windows, Armonk, NY, USA). The study protocol for utilizing the KAERS database was approved by KIDS (No.2007A0051) and the institutional review board of CHA University (Pocheon, South Korea).ResultsTotal of 4,215 AE records associated with anti‐obesity agents were identified, and the most etiologic anti‐obesity agent was phentermine (n=1,385; 32.8%), followed by liraglutide (n=1,155; 27.4%) and lorcaserin (n=690; 16.3%). AEs were frequently reported in females (n=3,458; 88.7%) and patients in their 30s (n=761; 18.1%) or 40s (n=672; 15.9%) of age. The prevalence of SAE was 2.5% (n=105). The highest number of nonserious AEs was gastro‐intestinal system disorders (n=1,233; 30.0%), followed by central &amp; peripheral nervous system disorders (n=782; 19.0%) and psychiatric disorders (n=682; 16.6%). The most common SAEs were associated with psychiatric disorders (n=27; 25.7%), central &amp; peripheral nervous system disorders (n=20; 19.0%), and gastrointestinal system disorders (n=13; 12.4%). The reporting odds ratio of SAE in liver and biliary system disorders from anti‐obesity agent administration was 3.145 (95% CI 6.689‐ 80.557). Factors associated with significantly elevated risk of SAEs was male sex (odds ratio (OR) 6.318; 95% CI 3.583‐10.839), triple agent therapy (OR 3.49; 95% CI:1.481‐8.170), increasing number of medications (OR 1.381; 95% CI 1.204‐1.583), and concomitant administration of fluoxetine (OR 5.146; 95% CI 2.570‐10.268).ConclusionThis is the first study of the study investigating AEs induced by medications primarily prescribed for weight loss by utilizing nationwide spontaneous adverse event reporting system. AEs induced by anti‐obesity agents are most frequently reported with phentermine and liraglutides, primarily manifested by gastrointestinal system disorders. SAEs are substantially associated with male gender, polypharmacy, and type of concomitant medications.

Brain Serotonin Deficiency and Fluoxetine Lead to Sex‐Specific Effects on Binge Eating in Mice

Binge eating disorder (BED), the most common eating disorder in the USA, negatively impacts psychological and physical health. Although the neurobiological basis of BED remains unknown, serotonergic dysfunction has been hypothesized to contribute to this condition. This study tested the hypothesis that brain serotonin deficiency will increase binge eating and block reductions in binge eating induced by fluoxetine. Binge eating was measured in wild‐type and serotonin‐deficient mice after acute and chronic fluoxetine administration. RNA was isolated from the raphe, and real‐time PCR was performed to evaluate gene expression. Males with low serotonin binge ate more than wild‐type mice at baseline, and fluoxetine reduced binge eating in both genotypes. Gene expression analyses revealed no significant genotype or drug effects on p11 expression in males, but fluoxetine significantly reduced the expression of 5HT1A receptor but not 5HT2A. In females, fluoxetine reduced binge eating in wild‐type but not serotonin‐deficient mice, and no baseline difference in binge eating was observed. Real‐time PCR revealed no significant main effects of genotype or drug on p11, 5HT1A, or 5HT2A expression. However, a significant genotype by drug interaction was observed for p11 expression in which fluoxetine reduced p11 expression in wild‐type mice and increased it in serotonin‐deficient animals. These results highlight the importance of sex as a modifying factor in the relationship between binge eating and serotonin levels and suggest that serotonin deficiency can modify sensitivity to fluoxetine‐induced reductions in binge eating, perhaps by impacting transcriptional responses to fluoxetine.

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25µg/kg, p.o.) for 7days, similar to fluoxetine (10mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100mg/kg, i.p., for 4days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.