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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360959

RESUMO

BACKGROUND: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. METHODS: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. RESULTS: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. CONCLUSIONS: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.


Assuntos
Encéfalo/efeitos dos fármacos , Creatina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Serotonina/metabolismo , Animais , Encéfalo/metabolismo , Creatina/administração & dosagem , Creatina/farmacologia , Suplementos Nutricionais , Sinergismo Farmacológico , Metabolismo Energético , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Fatores Sexuais
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361754

RESUMO

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.


Assuntos
Antipsicóticos/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Indóis/farmacologia , Nootrópicos/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Triptaminas/farmacologia , Animais , Antipsicóticos/síntese química , Família 2 do Citocromo P450/metabolismo , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/síntese química , Células Hep G2 , Humanos , Indóis/síntese química , Ligantes , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Nootrópicos/síntese química , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inibidores de Captação de Serotonina/síntese química , Relação Estrutura-Atividade , Triptaminas/síntese química
3.
Lancet Psychiatry ; 8(9): 824-835, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34419187

RESUMO

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based.


Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Humanos , Inibidores de Captação de Serotonina/farmacologia , Resultado do Tratamento
4.
Nat Commun ; 12(1): 5063, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417466

RESUMO

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.


Assuntos
Antidepressivos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Cloridrato de Vilazodona/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Sítios de Ligação , Células COS , Chlorocebus aethiops , Humanos , Cinética , Simulação de Dinâmica Molecular , Proteínas Mutantes/metabolismo , Mutação/genética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/ultraestrutura
5.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361040

RESUMO

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02-8.7 µM) and NET inhibitors (IC50 = 0.03-4.6 µM), and exhibited no SERT activity at concentrations < 10 µM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17-0.18 µM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264-356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.


Assuntos
Alcaloides/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Psicotrópicos/química , Pirrolidinas/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Alcaloides/farmacologia , Monoaminas Biogênicas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células HEK293 , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Psicotrópicos/farmacologia , Pirrolidinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia
6.
Acta Psychiatr Scand ; 144(3): 300-309, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34146343

RESUMO

OBJECTIVE: Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that effect sizes as high as 0.875 are necessary for a minimal clinically important difference. Whether such effect sizes are achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what effect sizes are theoretically achievable in placebo-controlled trials of antidepressants. METHODS: Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes for simulated antidepressant therapies to placebo-treated participants (n = 2201) from clinical trials of selective serotonin reuptake inhibitors. RESULTS: An optimally effective antidepressant, where all treated participants achieve HDRS-17 scores comparable to those displayed by healthy volunteers (remission-type model), had a maximum effect size of 1.75, with a mean difference of 11.6 points on the HDRS-17. In simulations where patients received an additional 50% symptom reduction over that obtained with placebo (improvement-type model), the maximum effect size was 1.08 with a mean HDRS-17 difference of 7.2. When adjusting for normal rates of treatment discontinuation, maximum effect sizes were 1.10 (remission-type model) and 0.76 (improvement-type model) with HDRS-17 mean differences of 8.8 and 5.6, respectively. CONCLUSIONS: Three methodological issues (i) a large and variable placebo response, (ii) a high rate of dropout and (iii) HDRS-17-ratings significantly larger than zero in healthy volunteers, reduce the degree of treatment-placebo separation achievable in depression trials. Assuming that those who discontinue treatment have only partial response, even a highly effective antidepressant would have difficulties surpassing such effect size cut-offs as have been suggested to signify a minimal clinically important difference.


Assuntos
Antidepressivos , Inibidores de Captação de Serotonina , Antidepressivos/uso terapêutico , Humanos , Efeito Placebo , Psicoterapia , Inibidores de Captação de Serotonina/farmacologia
7.
J Biol Chem ; 297(1): 100863, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118233

RESUMO

The serotonin transporter (SERT) shapes serotonergic neurotransmission by retrieving its eponymous substrate from the synaptic cleft. Ligands that discriminate between SERT and its close relative, the dopamine transporter DAT, differ in their association rate constant rather than their dissociation rate. The structural basis for this phenomenon is not known. Here we examined the hypothesis that the extracellular loops 2 (EL2) and 4 (EL4) limit access to the ligand-binding site of SERT. We employed an antibody directed against EL4 (residues 388-400) and the antibody fragments 8B6 scFv (directed against EL2 and EL4) and 15B8 Fab (directed against EL2) and analyzed their effects on the transport cycle of and inhibitor binding to SERT. Electrophysiological recordings showed that the EL4 antibody and 8B6 scFv impeded the initial substrate-induced transition from the outward to the inward-facing conformation but not the forward cycling mode of SERT. In contrast, binding of radiolabeled inhibitors to SERT was enhanced by either EL4- or EL2-directed antibodies. We confirmed this observation by determining the association and dissociation rate of the DAT-selective inhibitor methylphenidate via electrophysiological recordings; occupancy of EL2 with 15B8 Fab enhanced the affinity of SERT for methylphenidate by accelerating its binding. Based on these observations, we conclude that (i) EL4 undergoes a major movement during the transition from the outward to the inward-facing state, and (ii) EL2 and EL4 limit access of inhibitors to the binding of SERT, thus acting as a selectivity filter. This insight has repercussions for drug development.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas de Membrana Transportadoras/genética , Conformação Proteica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia , Sequência de Aminoácidos/genética , Animais , Sítios de Ligação/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/ultraestrutura , Células HEK293 , Humanos , Ligantes , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/ultraestrutura , Técnicas de Patch-Clamp , Domínios Proteicos/genética , Serotonina/química , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/ultraestrutura , Inibidores de Captação de Serotonina/química
8.
FASEB J ; 35(7): e21519, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34137477

RESUMO

Globally, COPD remains a major cause of disability and death. In the United States alone, it is estimated that approximately 14 million people suffer from the disease. Given the high disease burden and requirement for chronic, long-term medical care associated with COPD, it is essential that new disease modifying agents are developed to complement the symptomatic therapeutics currently available. In the present report, we have identified a potentially novel therapeutic agent through the use of a high throughput screen based on the knowledge that cigarette smoke induces the proteolytic enzyme MMP1 leading to destruction of the lung in COPD. A construct utilizing the cigarette responsive promoter element of MMP-1 was conjugated to a luciferase reporter and utilized in an in vitro assay to screen the NIH Molecular Libraries Small Molecule Repository to identify putative targets that suppressed luciferase expression in response to cigarette smoke extract (CSE). Selective serotonin reuptake inhibitors potently inhibited luciferase expression and were further validated. SSRI treatment suppressed MMP-1 production in small airway epithelial cells exposed to (CSE) in vitro as well as in smoke exposed rabbits. In addition, SSRI treatment inhibited inflammatory cytokine production while rescuing cigarette smoke induced downregulation in vivo of the anti-inflammatory lipid transporter ABCA1, previously shown by our laboratory to be lung protective. Importantly, SSRI treatment prevented lung destruction in smoke exposed rabbits as measured by morphometry. These studies support further investigation into SSRIs as a novel therapeutic for COPD may be warranted.


Assuntos
Fumar Cigarros/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metaloproteinase 1 da Matriz/química , Pneumonia/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacologia , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Pulmão/metabolismo , Pulmão/patologia , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , Coelhos , Serotonina/metabolismo
9.
Eur J Med Chem ; 220: 113533, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34049262

RESUMO

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.


Assuntos
Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Relação Dose-Resposta a Droga , Fluoxetina/síntese química , Fluoxetina/química , Fluvoxamina/síntese química , Fluvoxamina/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Inibidores de Captação de Serotonina/síntese química , Inibidores de Captação de Serotonina/química , Relação Estrutura-Atividade
10.
J Neuroimmunol ; 356: 577608, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000471

RESUMO

Fluoxetine is a selective serotonin reuptake inhibitor, which also has an immunomodulatory effect. We investigated the effects of fluoxetine and serotonin (5-HT) on the pro-inflammatory Th17- and Th1-cells in 30 patients with relapsing-remitting MS and 20 healthy subjects. Fluoxetine and 5-HT suppressed IL-17, IFN-γ and GM-CSF production by stimulated СD4+ T-cells in both groups. Blockade of 5-HT2B-receptors decreased the inhibitory effect of fluoxetine on cytokine production in MS patients. Finally, 5-HT2B-receptor activation inhibits IL-17, IFN-γ and GM-CSF production in both groups. These data suggest an anti-inflammatory role for fluoxetine in MS, which could be mediated by the activation of 5-HT2B-receptors.


Assuntos
Fluoxetina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Receptor 5-HT2B de Serotonina/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Feminino , Fluoxetina/farmacologia , Humanos , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Receptor 5-HT2B de Serotonina/imunologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Adulto Jovem
11.
J Affect Disord ; 290: 240-244, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34010748

RESUMO

BACKGROUND: Ketamine can act as antidepressant in patients with major depressive disorder (MDD) who are treatment-resistant. P11 has been implicated in ketamine's mechanism of action and proposed as biomarker for treatment response to other antidepressants. This study explores the effect of ketamine on peripheral p11 and the potential role for p11 as response marker for ketamine treatment. METHODS: Thirty Selective Serotonin Reuptake Inhibitor resistant MDD patients were randomized to either 0.5 mg/kg ketamine or placebo intravenous treatment. Using multicolor Flow Cytometry, peripheral p11 levels were measured before and 1-2 days after treatment. RESULTS: P11 levels were decreased within the ketamine group in both cytotoxic T cell and T helper cells populations, although this did not significantly differ from changes seen in the placebo group. Baseline p11 levels in cytotoxic T cells were significantly correlated with antidepressant response to ketamine treatment. LIMITATIONS: This study was part of a larger study examining the effect of ketamine on the serotonin system in MDD patients, therefore the number of study subjects was limited to that of the primary study. CONCLUSIONS: High baseline p11 levels in cytotoxic T cells were associated with a stronger reduction of depressive symptoms in MDD patients after ketamine treatment. Future studies should confirm if peripheral p11 levels could be used as a predictor of ketamine treatment response.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico
12.
Brain Behav Immun ; 96: 63-72, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34010713

RESUMO

Clinical studies indicate that obese individuals have an increased risk of developing co-morbid depressive illness and that these patients have reduced responses to antidepressant therapy, including selective serotonin reuptake inhibitors (SSRIs). Obesity, a condition of chronic mild inflammation including obesity-induced neuroinflammation, is proposed to contribute to decreases in synaptic concentrations of neurotransmitters like serotonin (5HT) by decreasing 5HT synthesis in the dorsal raphe nucleus (DRN) and/or affecting 5HT reuptake in DRN target regions like the hippocampus. In view of these observations, the goal of the current study was to examine inflammatory markers and serotonergic dynamics in co-morbid obesity and depression. Biochemical and behavioral assays revealed that high-fat diet produced an obesity and depressive-like phenotype in one cohort of rats and that these changes were marked by increases in key pro-inflammatory cytokines in the hippocampus. In real time using fast scan cyclic voltammetry (FSCV), we observed no changes in basal levels of hippocampal 5HT; however responses to escitalopram were significantly impaired in the hippocampus of obese rats compared to diet resistant rats and control rats. Further studies revealed that these neurochemical observations could be explained by increases in serotonin transporter (SERT) expression in the hippocampus driven by elevated neuroinflammation. Collectively, these results demonstrate that obesity-induced increases in neuroinflammation adversely affect SERT expression in the hippocampus of obese rats, thereby providing a potential synaptic mechanism for reduced SSRI responsiveness in obese subjects with co-morbid depressive illness.


Assuntos
Citalopram , Dieta Hiperlipídica , Animais , Citalopram/farmacologia , Hipocampo , Humanos , Obesidade/complicações , Ratos , Inibidores de Captação de Serotonina/farmacologia
13.
Transl Psychiatry ; 11(1): 268, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947833

RESUMO

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring's exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams' and pups' anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams' anxiety. Interestingly though, pups' exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.


Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Lactação/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Estresse Psicológico/fisiopatologia , Animais , COVID-19 , Citalopram/administração & dosagem , Citalopram/farmacologia , Citalopram/uso terapêutico , Crataegus , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pandemias , Gravidez , Inibidores de Captação de Serotonina/farmacologia , Xenobióticos/metabolismo
14.
Molecules ; 26(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917953

RESUMO

It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although their amount is not altered, which is possibly caused by higher endogenous ACh levels, which consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged as possible targets for SSRIs. Studies on dorsal raphe nucleus serotoninergic neurons support the concept that SSRI-induced nAChR inhibition decreases the glutamatergic hyperstimulation observed in stress conditions, which compensates the excessive 5-HT overflow in these neurons and, consequently, ameliorates depression symptoms. At the molecular level, SSRIs inhibit different nAChR subtypes by noncompetitive mechanisms, including ion channel blockade and induction of receptor desensitization, whereas α9α10 nAChRs, which are peripherally expressed and not directly involved in depression, are inhibited by competitive mechanisms. According to the functional and structural results, SSRIs bind within the nAChR ion channel at high-affinity sites that are spread out between serine and valine rings. In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed in different neurotransmitter systems widens the complexity by which these antidepressants may act clinically.


Assuntos
Antidepressivos/farmacologia , Receptores Nicotínicos/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/química , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Humanos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Inibidores de Captação de Serotonina/química , Fumar/efeitos adversos
15.
Asian J Psychiatr ; 59: 102637, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33836319

RESUMO

Abnormal indices of cell cycle regulation have been reported in multiple psychiatric disorders. Though reports specific to Obsessive Compulsive Disorder (OCD) are scant, numerous studies have highlighted partly common underlying biology in psychiatric disorders, cell cycle regulation being one such process. In this study, we therefore aimed to explore cell cycle in OCD. To the best of our knowledge, this is the first study to investigate these effects in OCD. We also evaluated the effect of in vitro fluoxetine, commonly used serotonin reuptake inhibitor (SRI) in OCD patients, on cell cycle regulation. The effects of both disease (OCD) and treatment (SRI) were assessed using lymphoblastoid cell lines (LCLs), derived from OCD patients and healthy controls, as a model system. LCLs were treated with 10µM of fluoxetine for 24 h, and the percentage of cells in each phase of the cell cycle was determined by flow cytometry. We observed a lower proportion of cells in the G2/M phase in OCD cases than controls. The findings suggest that cell cycle dysregulation could be peripheral cellular phenotype for OCD. Among cases, all of whom had been systematically characterized for SRI treatment response, LCLs from non-responders to SRI treatment had a lower proportion of cells in G2/M phase than responders.


Assuntos
Transtorno Obsessivo-Compulsivo , Divisão Celular , Fluoxetina/farmacologia , Humanos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Fenótipo , Inibidores de Captação de Serotonina/farmacologia , Resultado do Tratamento
16.
Sci Rep ; 11(1): 5890, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723270

RESUMO

To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 µg/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.


Assuntos
Antivirais/farmacologia , COVID-19/virologia , Fluoxetina/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/virologia , SARS-CoV-2/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Linhagem Celular , Células Cultivadas , Fluoxetina/uso terapêutico , Humanos , Pulmão/patologia , Inibidores de Captação de Serotonina/uso terapêutico , Replicação Viral/efeitos dos fármacos
17.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572981

RESUMO

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Citalopram/farmacologia , Cloridrato de Lurasidona/farmacologia , Receptores de Serotonina/metabolismo , Vortioxetina/farmacologia , Animais , Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citalopram/administração & dosagem , Ácido Glutâmico/metabolismo , Cloridrato de Lurasidona/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Vortioxetina/administração & dosagem
18.
Aging (Albany NY) ; 13(6): 8720-8736, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619236

RESUMO

Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness and persisting beyond hospitalization, which is associated with reduced quality of life and increased mortality. Recently, we have developed a clinically relevant animal model of PICS based on two-hit hypothesis. However, the underlying mechanism remains unclear. Accumulating evidence has demonstrated that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Thus, this study investigated the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS. In addition, we tested whether fluoxetine treatment early following combined stress can prevent these anatomical and behavioral pathologies. In the present study, we confirmed our previous study that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. In summary, our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathology of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.


Assuntos
Estado Terminal , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Parvalbuminas/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Estresse Psicológico/metabolismo
19.
J Neurosci ; 41(12): 2723-2732, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33536200

RESUMO

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.SIGNIFICANCE STATEMENT The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.


Assuntos
Dopamina/metabolismo , Fluoxetina/farmacologia , Locomoção/efeitos dos fármacos , Motivação/efeitos dos fármacos , Fenótipo , Inibidores de Captação de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Locomoção/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Microdiálise/métodos , Motivação/fisiologia
20.
Psychopharmacology (Berl) ; 238(6): 1401-1415, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33594503

RESUMO

Depression resulted as an important factor associated with the myocardial infarction (MI) prognosis. Patients with MI also have a higher risk for developing depression. Although the issue of depression after MI has become a matter of clinical concern, the molecular mechanism underlying depression after MI remains unclear, whereby several strategies suggested have not got ideal effects, such as selective serotonin reuptake inhibitors. In this review, we summarized and discussed the occurrence mechanism of depression after MI, such as 5-hydroxytryptamine (5-HT) dysfunction, altered hypothalamus-pituitary-adrenal (HPA) axis function, gut microbiota imbalance, exosomal signal transduction, and inflammation. In addition, we offered a succinct overview of treatment, as well as some promising molecules especially from natural products for the treatment of depression after MI.


Assuntos
Depressão/tratamento farmacológico , Infarto do Miocárdio/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Microbioma Gastrointestinal/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia
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