RESUMEN
Chronic treatment with clomipramine, a tricyclic antidepressant drug, reduces symptoms of obsessive-compulsive disorder (OCD) and can influence the activity of the hypothalamic-pituitary-adrenal axis. However, little is known regarding the effects of acute clomipramine on the immediate expression of stress responses. Serotonergic drugs can elicit surfacing, a behavioral profile potentially related to toxicity in fish, although surfacing has not yet been observed after clomipramine exposure. The present study investigated the impact of acute exposure to clomipramine on basal and stress-induced behaviors in the novel tank test and cortisol levels in mixed-sex, wild-type, adult zebrafish (Danio rerio). The findings show clomipramine-exposed groups (regardless of stress exposure) spent much more time in the top of the novel tank and had significantly less overall motor activity in the behavioral task compared to the fish not exposed to the drug. Then, the dose-dependent effects of acute clomipramine on activity in the surface of the novel tank (top third of the top half) were investigated further. Clomipramine dose-dependently increased surface-dwelling and elicited a dose-dependent hypoactivity in overall motor behavior. There were no statistically significant differences in whole-body cortisol levels in either experiment. Like other serotonin-acting drugs, clomipramine strongly elicited surface-dwelling and depressed motor behavior in adult zebrafish. Additional testing is needed to elucidate whether surfacing represents a toxic state and how serotonin regulates surfacing.
Asunto(s)
Conducta Animal , Clomipramina , Relación Dosis-Respuesta a Droga , Hidrocortisona , Pez Cebra , Animales , Clomipramina/farmacología , Clomipramina/administración & dosificación , Conducta Animal/efectos de los fármacos , Hidrocortisona/metabolismo , Masculino , Femenino , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains.
Asunto(s)
Encéfalo , Imipramina , Fosforilcolina , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Animales , Imipramina/metabolismo , Ratones , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Fosforilcolina/metabolismo , Fosforilcolina/análogos & derivados , Masculino , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/metabolismo , Ratones Endogámicos C57BL , Análisis de Componente PrincipalRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory loss. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and antioxidant properties in the central nervous system. The aim of this study was to investigate the neuroprotective effects of imipramine on streptozotocin (STZ)-induced memory impairment. Male Wistar rats received an intracerebroventricular injection of STZ (3 mg/kg, 3 µl/ventricle) using the stereotaxic apparatus. The Morris water maze and passive avoidance tests were used to evaluate cognitive functions. 24 h after the STZ injection, imipramine was administered intraperitoneally at doses of 10 or 20 mg/kg for 14 consecutive days. The mRNA and protein levels of neurotrophic factors (BDNF and GDNF) and pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) were measured in the hippocampus using real-time PCR and ELISA techniques, respectively. In addition, real-time PCR was used to evaluate the mRNA levels of markers associated with neurogenesis (Nestin, DCX, and Ki67) and mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM). The results showed that imipramine, especially at a dose of 20 mg/kg, effectively improved STZ-induced memory impairment. This improvement was associated with an increase in neurogenesis and neurotrophic factors and a decrease in neuroinflammation and mitochondrial biogenesis dysfunction. Based on these results, imipramine appears to be a promising therapeutic option for improving cognitive functions in neurodegenerative diseases such as AD.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Hipocampo , Imipramina , Neurogénesis , Biogénesis de Organelos , Ratas Wistar , Estreptozocina , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Masculino , Neurogénesis/efectos de los fármacos , Imipramina/farmacología , Ratas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Proteína Doblecortina , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Memoria/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Antidepresivos Tricíclicos/farmacología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Citocinas/metabolismoRESUMEN
Tricyclic medicine such as amitriptyline (AMT) hydrochloride, initially developed to treat depression, is also used to treat neuropathic pain, anxiety disorder, and migraines. The mechanism of functioning of this type of drugs is ambiguous. Understanding the mechanism is important for designing new drug molecules with higher pharmacological efficiency. Hence, in the present study, biophysical approaches have been taken to shed light on their interactions with a model cellular membrane of brain sphingomyelin in the form of monolayer and multi-lamellar vesicles. The surface pressure-area isotherm infers the partitioning of a drug molecule into the lipid monolayer at the air water interface, providing a higher surface area per molecule and reducing the in-plane elasticity. Further, the surface electrostatic potential of the lipid monolayer is found to increase due to the insertion of drug molecule. The interfacial rheology revealed a reduction of the in-plane viscoelasticity of the lipid film, which, depends on the adsorption of the drug molecule onto the film. Small-angle X-ray scattering (SAXS) measurements on multilamellar vesicles (MLVs) have revealed that the AMT molecules partition into the hydrophobic core of the lipid membrane, modifying the organization of lipids in the membrane. The modified physical state of less rigid membrane and the transformed electrostatics of the membrane could influence its interaction with synaptic vesicles and neurotransmitters making higher availability of the neurotransmitters in the synaptic cleft.
Asunto(s)
Amitriptilina , Antidepresivos Tricíclicos , Esfingomielinas , Esfingomielinas/química , Antidepresivos Tricíclicos/química , Antidepresivos Tricíclicos/farmacología , Amitriptilina/química , Amitriptilina/metabolismo , Amitriptilina/farmacología , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Electricidad EstáticaRESUMEN
Some tricyclic antidepressants (TCAs), including amitriptyline (ATL), clomipramine (CLO), and desipramine (DES), are known to be effective for management of neuropathic pain. It was previously determined that ATL, CLO, and DES are capable of voltage-dependent blocking of NMDA receptors of glutamate (NMDAR), which play a key role in pathogenesis of neuropathic pain. Despite the similar structure of ATL, CLO, and DES, efficacy of their interaction with NMDAR varies significantly. In the study presented here, we applied molecular modeling methods to investigate the mechanism of binding of ATL, CLO, and DES to NMDAR and to identify structural features of the drugs that determine their inhibitory activity against NMDAR. Molecular docking of the studied TCAs into the NMDAR channel was performed. Conformational behavior of the obtained complexes in the lipid bilayer was simulated by the method of molecular dynamics (MD). A single binding site (upper) for the tertiary amines ATL and CLO and two binding sites (upper and lower) for the secondary amine DES were identified inside the NMDAR channel. The upper and lower binding sites are located along the channel axis at different distances from the extracellular side of the plasma membrane. MD simulation revealed that the position of DES in the lower site is stabilized only in the presence of sodium cation inside the NMDAR channel. DES binds more strongly to NMDAR compared to ATL and CLO due to simultaneous interaction of two hydrogen atoms of its cationic group with the asparagine residues of the ion pore of the receptor. This feature may be responsible for the stronger side effects of DES. It has been hypothesized that ATL binds to NMDAR less efficiently compared to DES and CLO due to its lower conformational mobility. The identified features of the structure- and cation-dependent mechanism of interaction between TCAs and NMDAR will help in the further development of effective and safe analgesic therapy.
Asunto(s)
Antidepresivos Tricíclicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/química , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/metabolismo , Antidepresivos Tricíclicos/química , Sitios de Unión , Amitriptilina/química , Amitriptilina/metabolismo , Amitriptilina/farmacología , Humanos , Clomipramina/farmacología , Clomipramina/química , Clomipramina/metabolismo , Cationes/metabolismo , Cationes/química , Desipramina/farmacología , Unión ProteicaRESUMEN
BACKGROUND AND OBJECTIVES: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts. METHODS: In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out. RESULTS: Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC) in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine. CONCLUSIONS: Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.
Asunto(s)
Antidepresivos Tricíclicos , Dotiepina , Ratas , Ratones , Animales , Masculino , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Clomipramina/farmacología , Doxepina/farmacología , Deuterio , Inhibidores Selectivos de la Recaptación de Serotonina , Ratas Wistar , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Serotonina/metabolismo , Modelos AnimalesRESUMEN
Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain.
Asunto(s)
Neuralgia , Humanos , Ratones , Animales , Neuralgia/tratamiento farmacológico , Antidepresivos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
Traditionally prescribed for mood disorders, tricyclic antidepressants (TCAs) have shown promising therapeutic effects on chronic neuralgia and irritable bowel syndrome. However, the mechanism by which these atypical effects manifest is unclear. Among the proposed mechanisms is the well-known pain-related inhibitory G-protein coupled receptor, namely the opioid receptor (OR). Here, we confirmed that TCA indeed stimulates OR and regulates the gating of TRPC4, a downstream signaling of the Gi-pathway. In an ELISA to quantify the amount of intracellular cAMP, a downstream product of OR/Gi-pathway, treatment with amitriptyline (AMI) showed a decrease in [cAMP]i similar to that of the µOR agonist. Next, we explored the binding site of TCA by modeling the previously revealed ligand-bound structure of µOR. A conserved aspartate residue of ORs was predicted to participate in salt bridge interaction with the amine group of TCAs, and in aspartate-to-arginine mutation, AMI did not decrease the FRET-based binding efficiency between the ORs and Gαi2. As an alternative way to monitor the downstream signaling of Gi-pathway, we evaluated the functional activity of TRPC4 channel, as it is well known to be activated by Gαi. TCAs increased the TRPC4 current through ORs, and TCA-evoked TRPC4 activation was abolished by an inhibitor of Gαi2 or its dominant-negative mutant. As expected, TCA-evoked activation of TRPC4 was not observed in the aspartate mutants of OR. Taken together, OR could be proclaimed as a promising target among numerous binding partners of TCA, and TCA-evoked TRPC4 activation may help to explain the nonopioid analgesic effect of TCA.NEW & NOTEWORTHY Endogenous opioid systems modulate pain perception, but concerns about opioid-related substance misuse limit their use. This study has raised TRPC4 channel as a candidate target for alternative analgesics, tricyclic antidepressants (TCAs). TCAs have been shown to bind to and activate opioid receptors (ORs), leading to downstream signaling pathways involving TRPC4. The functional selectivity and biased agonism of TCA towards TRPC4 in dependence on OR may provide a better understanding of its efficacy or side effects.
Asunto(s)
Analgésicos Opioides , Antidepresivos Tricíclicos , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Ácido Aspártico , Ligandos , Proteínas Portadoras , Amitriptilina/farmacología , Amitriptilina/uso terapéutico , Receptores OpioidesRESUMEN
Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming increasingly important in the biomedical field since enhancing CA activity may have beneficial effects at neurological level. Here, we investigate selected antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants (TCAs) as potential activators of human CAs I, II, IV, and VII. Our findings indicate that these compounds are more effective at activating hCA II and VII compared to hCA I and IV. Overall, hCA VII was the most efficiently activated isoform, particularly by phenothiazines and TCAs. This is especially relevant since hCA VII is the most abundant isoform in the central nervous system (CNS) and is implicated in neuronal signalling and bicarbonate balance regulation. This study offers additional insights into the pharmacological profiles of clinically employed drugs and sets the ground for the development of novel optimised CAAs.
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Antipsicóticos , Anhidrasas Carbónicas , Humanos , Antipsicóticos/farmacología , Antidepresivos Tricíclicos/farmacología , Anhidrasas Carbónicas/metabolismo , Isoformas de Proteínas/metabolismo , Fenotiazinas , Antagonistas de los Receptores Histamínicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.
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Hígado Graso , Enfermedades Metabólicas , Neoplasias , Ratones , Animales , Ácidos Grasos/metabolismo , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Antidepresivos Tricíclicos/metabolismo , Nortriptilina/metabolismo , Nortriptilina/uso terapéutico , Reposicionamiento de Medicamentos , Hígado Graso/patología , Enfermedades Metabólicas/metabolismo , Neoplasias/patología , Hígado/metabolismoRESUMEN
BACKGROUND: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation. OBJECTIVE: This study aimed to (i) examine the inhibitory effects of TCAs (viz., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing in vitro-in vivo extrapolation (IVIVE) approaches. METHOD: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the in vitro system containing 2% BSA. The Ki values were employed to predict the DDI magnitude in vivo by using static and dynamic mechanistic PBPK approaches Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective Ki values of 91 ± 7.5 and 82 ± 11 µM, 23 ± 1.3 and 14 ± 0.7 µM, 103 ± 5 and 90 ± 7 µM, and 115 ± 5 and 110 ± 3 µM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was <5% for amitriptyline or nortriptyline. PBPK modelling predicted an increase of less than 10% in the morphine AUC due to the inhibition of clomipramine and imipramine in both virtual healthy and cirrhotic populations. CONCLUSION: The results suggest that the likelihood of potential clinical DDIs arising from tricyclic antidepressant inhibition on morphine glucuronidation is low.
Asunto(s)
Antidepresivos Tricíclicos , Clomipramina , Humanos , Antidepresivos Tricíclicos/farmacología , Imipramina , Amitriptilina/farmacología , Nortriptilina/farmacología , Morfina/farmacología , HígadoRESUMEN
The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium−calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5−1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug−drug or ion−drug interaction when these medicines are used together therapeutically.
Asunto(s)
Amitriptilina , Antidepresivos Tricíclicos , Ratas , Animales , Antidepresivos Tricíclicos/farmacología , Amitriptilina/farmacología , Receptores de N-Metil-D-Aspartato , Litio/farmacología , Calcio/metabolismo , Desipramina/farmacología , Calcio de la DietaRESUMEN
Microbial diversity is reduced in the gut microbiota of animals and humans treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). The mechanisms driving the changes in microbial composition, while largely unknown, is critical to understand considering that the gut microbiota plays important roles in drug metabolism and brain function. Using Escherichia coli, we show that the SSRI fluoxetine and the TCA amitriptyline exert strong selection pressure for enhanced efflux activity of the AcrAB-TolC pump, a member of the resistance-nodulation-cell division (RND) superfamily of transporters. Sequencing spontaneous fluoxetine- and amitriptyline-resistant mutants revealed mutations in marR and lon, negative regulators of AcrAB-TolC expression. In line with the broad specificity of AcrAB-TolC pumps these mutants conferred resistance to several classes of antibiotics. We show that the converse also occurs, as spontaneous chloramphenicol-resistant mutants displayed cross-resistance to SSRIs and TCAs. Chemical-genomic screens identified deletions in marR and lon, confirming the results observed for the spontaneous resistant mutants. In addition, deletions in 35 genes with no known role in drug resistance were identified that conferred cross-resistance to antibiotics and several displayed enhanced efflux activities. These results indicate that combinations of specific antidepressants and antibiotics may have important effects when both are used simultaneously or successively as they can impose selection for common mechanisms of resistance. Our work suggests that selection for enhanced efflux activities is an important factor to consider in understanding the microbial diversity changes associated with antidepressant treatments. IMPORTANCE Antidepressants are prescribed broadly for psychiatric conditions to alter neuronal levels of synaptic neurotransmitters such as serotonin and norepinephrine. Two categories of antidepressants are selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs); both are among the most prescribed drugs in the United States. While it is well-established that antidepressants inhibit reuptake of neurotransmitters there is evidence that they also impact microbial diversity in the gastrointestinal tract. However, the mechanisms and therefore biological and clinical effects remain obscure. We demonstrate antidepressants may influence microbial diversity through strong selection for mutant bacteria with increased AcrAB-TolC activity, an efflux pump that removes antibiotics from cells. Furthermore, we identify a new group of genes that contribute to cross-resistance between antidepressants and antibiotics, several act by regulating efflux activity, underscoring overlapping mechanisms. Overall, this work provides new insights into bacterial responses to antidepressants important for understanding antidepressant treatment effects.
Asunto(s)
Proteínas de Escherichia coli , Escherichia coli , Humanos , Escherichia coli/genética , Inhibidores Selectivos de la Recaptación de Serotonina , Proteínas de Escherichia coli/metabolismo , Fluoxetina/metabolismo , Fluoxetina/farmacología , Antidepresivos Tricíclicos/metabolismo , Antidepresivos Tricíclicos/farmacología , Amitriptilina/farmacología , Antidepresivos/metabolismo , Antidepresivos/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
Since we previously discovered that simultaneous inhibition of cyclooxygenase-2 (COX-2; a highly inducible enzyme, crucial for the conversion of arachidonic acid to prostaglandin G2, which plays a predominant role in the CNS) by NS398 and metabotropic glutamate receptor 5 (mGluR5) through the use of its antagonist [3-((2-methyl-4-thiazolyl)ethyl)pyridine; MTEP] alters mouse behavior (e.g., affects spatial learning, and induces/intensifies the antidepressant effect), our aim was to discover the mechanism responsible for these changes. Down syndrome cell adhesion molecule (DSCAM), a member of the immunoglobulin cell adhesion molecule (Ig-CAM) superfamily, is involved in developing the central and peripheral nervous system by influencing cell adhesion mechanisms necessary for synaptic activity and plasticity. Since COX-2 has been implicated in several neuropsychiatric diseases (e.g., major depressive disorder) resulting from neuroplasticity disorders, and on the other hand, its expression is regulated by synaptic activity, we hypothesized that cognitive changes after administration of COX-2 inhibitor and mGluR5 antagonist might be a consequence of impaired DSCAM expression. Importantly, DSCAM deficiency leads to dysregulation of glutamatergic transmission and plasticity. In previous studies, we have demonstrated glutamatergic changes after NS398 and MTEP administration, further supporting the validity of our hypothesis. Due to the different effects observed in behavioral tests, this study used the prefrontal cortex (PFC) and hippocampus (HC) of C57BL/6J mice, which received NS398 and MTEP alone, or in combination, for 7 or 14 days. Among many properties, we also previously investigated the antidepressant potential of these compounds, so we used imipramine (a tricyclic antidepressant) as the reference drug. DSCAM mRNA expression was determined by qRT-PCR. Our results indicate that DSCAM expression after administration of MTEP and NS398 and imipramine along with NS398 is structure- and time-dependent.
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Trastorno Depresivo Mayor , Receptor del Glutamato Metabotropico 5 , Animales , Antidepresivos/farmacología , Antidepresivos Tricíclicos/farmacología , Ácido Araquidónico , Adhesión Celular , Moléculas de Adhesión Celular , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Imipramina/farmacología , Ratones , Ratones Endogámicos C57BL , Nitrobencenos , Piridinas/farmacología , ARN Mensajero , Sulfonamidas , Tiazoles/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Amitriptyline (AM) is a classical and typical tricyclic antidepressant drug. Despite its well-known effects on the nervous system, it has been described to work as a TLR4 antagonist and several clinical works suggested some unexpected cardiovascular effects. The role of amitriptyline on vascular tone is not clear, thus we hypothesized that amitriptyline has a double effect on vascular tone by both endothelial TLR4-dependent nitric oxide down-regulation and calcium channel blockade in smooth muscle cells. EXPERIMENTAL APPROACH: Changes in isometric tension were recorded on a wire myograph. NO production was evaluated by fluorescence microscopy and flow cytometry in the mouse aorta and EAhy926 cells using DAF fluorescence intensity. Calcium influx was evaluated in A7r5 cells by flow cytometry. Western blot was used to analyze eNOS and nNOS phosphorylation. KEY RESULTS: AM reduced PE-induced contraction by calcium influx diminution in smooth muscle cells (F/F0 = 225.6 ± 15.9 and 118.6 ± 17.6 to CT and AM, respectively). AM impaired Ach-dependent vasodilation (Emax = 95.8 ± 1.4; 78.1 ± 1.8; 60.4 ± 2.9 and -7.4 ± 1.0 for CT, 0.01, 0,1 and 1 µmol/L AM, respectively) through reduction of calcium influx and NO availability and TLR4 antagonism in a concentration-dependent manner. AM or TLR4 gene deletion significantly reduced NO production (Fluorescence = 9503 ± 871.7, 2561 ± 282, 4771 ± 728 and 1029 ± 103 to CT, AM, TLR4-/- and AM + TLR4-/-, respectively) by an increase in nNOSser852 and reduction in eNOSser1177 phosphorylation in endothelial cells. CONCLUSIONS AND IMPLICATIONS: Our data show that amitriptyline impaired vascular function through two different mechanisms: blockade of TLR4 in endothelial cells and consequent decrease in NO production and calcium influx reduction in smooth muscle and endothelial cells. We also suggest, for the first time, nNOS activity reduction by AM in non-neuronal cells.
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Canales de Calcio , Células Endoteliales , Ratones , Animales , Amitriptilina/farmacología , Receptor Toll-Like 4 , Óxido Nítrico/metabolismo , Endotelio Vascular , Calcio/metabolismo , Antidepresivos Tricíclicos/farmacología , Ratones Endogámicos C57BL , Vasodilatación , Miocitos del Músculo Liso/metabolismoRESUMEN
INTRODUCTION: Mental disorders and psychotropic medications are known to increase the risk of osteoporosis and fractures. However, current evidence is mostly limited to studies that used bone mineral density (BMD), which does not provide information about the texture of bone tissue and can underestimate fracture risk. METHODS: We tested the association between bone texture, as measured with lumbar spine trabecular bone score (TBS), and both diagnosed mental disorders and psychotropic medication use in a large population-based BMD registry from Manitoba, Canada. General linear and logistic regression models were used to test the association of TBS with mental disorders (anxiety, depression, schizophrenia, and alcohol use disorder) and psychotropic medications use (selective serotonin reuptake inhibitors [SSRI], tricyclic antidepressants [TCA], other antidepressants, lithium, nonlithium mood stabilizers, antipsychotics, and benzodiazepines), adjusted for comorbidities and confounding factors. RESULTS: The study population contained 45,716 women (mean age = 64.1, SD = 10.4), which included 21.1 % with diagnoses for mental disorders and 18.7 % using psychotropic medications. We observed significant negative covariate-adjusted effects on TBS from diagnosed alcohol use disorder (3.1 % reduction in TBS, p < 0.001) and exposure to SSRI (0.6 % reduction, p < 0.001), TCA (0.8 % reduction, p < 0.001), other antidepressants (0.8 % reduction, p < 0.001), and lithium (3 % reduction, p < 0.001). Logistic regression revealed that TBS in the lowest (versus highest) tertile was associated with alcohol use disorder (adjusted odds ratio [OR] = 2.87, 95 % confidence interval [CI]: 1.95, 4.21), exposure to SSRI (OR = 1.21; 95 % CI: 1.08, 1.35), TCA (OR = 1.18, 95 % confidence interval [CI]: 1.04, 1.35), other antidepressants (OR = 1.26; 95 % CI: 1.09, 1.45), and lithium (OR = 1.97; 95 % CI: 1.09, 3.57). CONCLUSION: Our results suggest that alcohol use disorder, antidepressants, and lithium are associated with poorer bone texture in women. These findings add to the current literature on the link of bone pathology with mental disorders and psychotropic medications.
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Alcoholismo , Fracturas Óseas , Trastornos Mentales , Fracturas Osteoporóticas , Humanos , Femenino , Persona de Mediana Edad , Hueso Esponjoso/diagnóstico por imagen , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Alcoholismo/tratamiento farmacológico , Densidad Ósea , Vértebras Lumbares , Fracturas Óseas/epidemiología , Trastornos Mentales/complicaciones , Trastornos Mentales/tratamiento farmacológico , Antidepresivos/uso terapéutico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Absorciometría de Fotón/métodos , Fracturas Osteoporóticas/epidemiologíaRESUMEN
RATIONALE: The pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson's disease under chronic L-DOPA therapy are insufficiently explored. OBJECTIVES: The aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion. METHODS: The antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method. RESULTS: Desipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus. CONCLUSIONS: The performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson's disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.
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Levodopa , Enfermedad de Parkinson , Animales , Ratas , Levodopa/farmacología , Oxidopamina , Antidepresivos Tricíclicos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Desipramina/farmacología , Dopamina/metabolismo , Serotonina/metabolismo , Antipruriginosos/metabolismo , Antipruriginosos/farmacología , Inhibidores de Agregación Plaquetaria/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Antiparkinsonianos/farmacología , Antiparkinsonianos/metabolismo , Cuerpo Estriado , Norepinefrina/metabolismoRESUMEN
BACKGROUND: Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α1 -adrenergic receptors such as doxazosin, tamsulosin, and prazosin. OBJECTIVES: To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions. METHODS: The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed. RESULTS: 6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS. DISCUSSION AND CONCLUSION: 6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α1 -adrenergic receptor antagonists.
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Dopamina , Conducto Deferente , Antagonistas Adrenérgicos/farmacología , Amitriptilina/farmacología , Animales , Antidepresivos Tricíclicos/farmacología , Carbamazepina/farmacología , Cromatografía Liquida , Desipramina/farmacología , Dopamina/análogos & derivados , Dopamina/farmacología , Doxazosina/farmacología , Epinefrina/farmacología , Humanos , Masculino , Contracción Muscular , Músculo Liso , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico , Norepinefrina/farmacología , Prazosina/farmacología , Ratas , Receptores Adrenérgicos , Tamsulosina/farmacología , Espectrometría de Masas en TándemRESUMEN
6-Nitrodopamine (6-ND) is released by rat vas deferens and exerts a potent contractile response that is antagonized by tricyclic antidepressants and α1-, ß1- and ß1/ß2-adrenoceptor antagonists. The release of 6-ND, noradrenaline, adrenaline and dopamine from rat isolated right atria was assessed by tandem mass spectrometry. The effects of the catecholamines were evaluated in both rat isolated right atria and in anaesthetized rats. 6-ND was the major catecholamine released from the isolated atria and the release was significantly reduced in nitric oxide synthase inhibitor L-NAME pre-treated atria or in atria obtained from L-NAME chronically treated animals, but unaffected by tetrodotoxin. 6-ND (1 pM) significantly increased the atrial frequency, being 100 times more potent than noradrenaline and adrenaline. Selective ß1-blockers reduced the atrial frequency only at concentrations that prevented the increases in atrial frequency induced by 6-ND 1pM. Conversely, ß1-blockade did not affect dopamine (10 nM), noradrenaline (100 pM) or adrenaline (100 pM) effect. The reductions in atrial frequency induced by the ß1-adrenoceptor antagonists were absent in L-NAME pre-treated atria and in atria obtained from chronic L-NAME-treated animals. Tetrodotoxin did not prevent the reduction in atrial frequency induced by L-NAME or by ß1-blockers treated preparations. In anaesthetized rats, at 1 pmol/kg, only 6-ND caused a significant increase in heart rate. Inhibition of 6-ND synthesis by chronic L-NAME treatment reduced both atrial frequency and heart rate. The results indicate that 6-ND is a major modulator of rat heart chronotropism and the reduction in heart rate caused by ß1-blockers are due to selective blockade of 6-ND receptor.
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Antidepresivos Tricíclicos , Dopamina , Antagonistas Adrenérgicos beta/farmacología , Animales , Antidepresivos Tricíclicos/farmacología , Catecolaminas , Dopamina/análogos & derivados , Dopamina/farmacología , Epinefrina/farmacología , Atrios Cardíacos , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa , Norepinefrina/farmacología , Ratas , Receptores Adrenérgicos , Tetrodotoxina/farmacologíaRESUMEN
Epigallocatechin 3-gallate (EGCG) is a natural polyphenolic antioxidant in green tea leaves with well-known health-promoting properties. However, the influence of EGCG on a chronic animal model of depression remains to be fully investigated, and the details of the molecular and cellular changes are still unclear. Therefore, the present study aimed to investigate the antidepressant effect of EGCG in mice subjected to chronic unpredictable mild stress (CUMS). After eight consecutive weeks of CUMS, the mice were treated with EGCG (200 mg/kg b.w.) by oral gavage for two weeks. A forced swimming test (FST) was used to assess depressive symptoms. EGCG administration significantly alleviated CUMS-induced depression-like behavior in mice. EGCG also effectively decreased serum interleukin-1ß (IL-1ß) and increased the mRNA expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampal CA3 region of CUMS mice. Furthermore, electron microscopic examination of CA3 neurons in CUMS mice showed morphological features of apoptosis, loss or disruption of the myelin sheath, and degenerating synapses. These neuronal injuries were diminished with the administration of EGCG. The treatment effect of EGCG in CUMS-induced behavioral alterations was comparable with that of clomipramine hydrochloride (Anafranil), a tricyclic antidepressant drug. In conclusion, our study demonstrates that the antidepressive action of EGCG involves downregulation of serum IL-1ß, upregulation of BDNF mRNA in the hippocampus, and reduction of CA3 neuronal lesions.