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The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS, and only subtle-altered A-to-I RNA editing of Htr2c mRNAs was uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid-a metabolite of dopamine-was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes in monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single-cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.
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Encéfalo , Síndrome de Prader-Willi , Ratones , Animales , Encéfalo/metabolismo , Neuronas/metabolismo , Dopamina/metabolismo , Corteza Prefrontal/metabolismo , Serotonina/metabolismo , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismoRESUMEN
Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.
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Corticosterona , Modelos Animales de Enfermedad , Hipocampo , Memoria a Largo Plazo , Receptor de Nociceptina , Nociceptina , Péptidos Opioides , Receptores Opioides , Estrés Psicológico , Animales , Receptores Opioides/metabolismo , Ratones , Estrés Psicológico/metabolismo , Masculino , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Péptidos Opioides/metabolismo , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Antagonistas de Narcóticos/farmacología , Ratones Endogámicos C57BL , Cognición/efectos de los fármacos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/tratamiento farmacológicoRESUMEN
This review highlights the advantages of high-precision liquid chromatography with an electrochemical detector (HPLC-ECD) in detecting and quantifying biological samples obtained through intracerebral microdialysis, specifically the serotonergic and dopaminergic systems: Serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), 3-metoxytryptamin (3-MT) and homovanillic acid (HVA). Recognized for its speed and selectivity, HPLC enables direct analysis of intracerebral microdialysis samples without complex derivatization. Various chromatographic methods, including reverse phase (RP), are explored for neurotransmitters (NTs) and metabolites separation. Electrochemical detector (ECD), particularly with glassy carbon (GC) electrodes, is emphasized for its simplicity and sensitivity, aimed at enhancing reproducibility through optimization strategies such as modified electrode materials. This paper underscores the determination of limits of detection (LOD) and quantification (LOQ) and the linear range (L.R.) showcasing the potential for real-time monitoring of compounds concentrations. A non-exhaustive compilation of literature values for LOD, LOQ, and L.R. from recent publications is included.
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Dopamina , Serotonina , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Dopamina/metabolismo , Cromatografía Liquida , Serotonina/metabolismo , Neurotransmisores , Ácido 3,4-Dihidroxifenilacético/metabolismo , Ácido Hidroxiindolacético/análisis , Ácido Hidroxiindolacético/metabolismo , Monoaminas BiogénicasRESUMEN
Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.
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Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression.
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Astrocitos , Conexinas , Trastorno Depresivo , Animales , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Carbenoxolona/farmacología , Conexinas/efectos de los fármacos , Conexinas/metabolismo , Fenotipo , Recurrencia , Depresión/tratamiento farmacológico , Depresión/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismoRESUMEN
Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.
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Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Anhedonia/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacocinética , Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Fluoxetina/uso terapéutico , Humanos , Masculino , Memoria/efectos de los fármacos , RatonesRESUMEN
The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.
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Ansiedad/tratamiento farmacológico , Corticosterona/farmacología , Trastorno Depresivo/tratamiento farmacológico , Estrés Psicológico/tratamiento farmacológico , Animales , Antidepresivos/farmacología , Ansiedad/fisiopatología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/patología , Conducta Animal/efectos de los fármacos , Trastorno Depresivo/patología , Modelos Animales de Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/patología , Ratones , Fenotipo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/patología , Estrés Psicológico/patología , NataciónRESUMEN
Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.
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Aminoácidos de Cadena Ramificada/sangre , Ansiolíticos/uso terapéutico , Antidepresivos/uso terapéutico , Resistencia a la Insulina/fisiología , Metformina/uso terapéutico , Aminoácidos de Cadena Ramificada/antagonistas & inhibidores , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Ansiedad/sangre , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Depresión/sangre , Depresión/tratamiento farmacológico , Depresión/psicología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos C57BLRESUMEN
Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP-like sites present in the genome. However, most studies reporting the consequences of Cre-lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data. In this study, we report the anatomical, neurochemical, and behavioral consequences in mice of adeno-associated virus (AAV)-mediated Cre expression in the dopaminergic nuclei substantia nigra, at commonly used viral titers (3 × 109 genome copies/0.3 µL or 2 × 109 genome copies/0.6 µL). We found that injecting AAV-eGFP-Cre into the SN engendered drastic and reproducible modifications of behavior, with increased basal locomotor activity as well as impaired locomotor response to cocaine compared to AAV-eGFP-injected controls. Cre expression in the SN induced a massive decrease in neuronal populations of both pars compacta and pars reticulata and dopamine depletion in the nigrostriatal pathway. This anatomical injury was associated with typical features of programmed cell death, including an increase in DNA break markers, evidence of apoptosis, and disrupted macroautophagy. These observations underscore the need for careful control of Cre toxicity in the brain and the reassessment of previous studies. In addition, our findings suggest that Cre-mediated ablation may constitute an efficient tool to explore the function of specific cell populations and areas in the brain, and the impact of neurodegeneration in these populations.
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Integrasas , Neuronas/patología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Animales , Apoptosis/efectos de los fármacos , Dependovirus , Dopamina/metabolismo , Vectores Genéticos , Integrasas/administración & dosificación , Integrasas/genética , Integrasas/toxicidad , Locomoción/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
The serotonin receptor subtypes 2 comprise 5-HT2A, 5-HT2B, and 5-HT2C, which are Gαq-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT2 receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT2C receptors interact with either 5-HT2A or 5-HT2B receptors. Although heterodimerization with 5-HT2C receptors does not alter 5-HT2C Gαq-dependent inositol phosphate signaling, 5-HT2A or 5-HT2B receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT2C on 5-HT2A and 5-HT2B receptor binding; in 5-HT2C-containing heterodimers, ligands bind and activate the 5-HT2C protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT2 receptor heterodimerization in vivo Accordingly, exogenous expression of an inactive form of the 5-HT2C receptor in the locus ceruleus is associated with decreased 5-HT2A-dependent noradrenergic transmission. These data demonstrate that 5-HT2 receptors can form functionally asymmetric heterodimers in vitro and in vivo that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT2 receptors are co-expressed.
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Locus Coeruleus/metabolismo , Receptores de Serotonina 5-HT2/metabolismo , Transmisión Sináptica/fisiología , Animales , Células CHO , Células COS , Chlorocebus aethiops , Cricetulus , Células HEK293 , Humanos , Masculino , Ratones , Multimerización de Proteína , Receptores de Serotonina 5-HT2/genéticaRESUMEN
Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.
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Parvalbúminas , Inhibidores Selectivos de la Recaptación de Serotonina , Ratones , Masculino , Animales , Clorhidrato de Venlafaxina/farmacología , Parvalbúminas/metabolismo , Serotonina/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Antidepresivos/metabolismo , Interneuronas/metabolismoRESUMEN
Type 2 diabetes and obesity characterized by hallmarks of insulin resistance along with an imbalance in brain oxidative metabolism would impair intrinsic capacities (ICs), a new concept for assessing mental and physical functioning. Here, we explored the impact of physical activity on antioxidant responses and oxidative metabolism in discrete brain areas of HFD or standard diet (STD) fed mice but also its consequences on specific domains of ICs. 6-week-old Swiss male mice were exposed to a STD or a HFD for 16 weeks and half of the mice in each group had access to an activity wheel and the other half did not. As expected HFD mice displayed peripheral insulin resistance but also a persistent inhibition of aconitase activity in cortices revealing an increase in mitochondrial reactive oxygen species (ROS) production. Animals with access to the running wheel displayed an improvement of insulin sensitivity regardless of the diet factor whereas ROS production remained impaired. Moreover, although the access of the running wheel did not influence mitochondrial biomass, in the oxidative metabolism area, it produced a slight decrease in brain SOD1 and catalase expression notably in HFD fed mice. At the behavioural level, physical exercise produced anxiolytic/antidepressant-like responses and improved motor coordination in both STD and HFD fed mice. However, this non-pharmacological intervention failed to enhance cognitive performance. These findings paint a contrasting landscape about physical exercise as a non-pharmacological intervention for positively orienting the aging trajectory.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Masculino , Ratones , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/fisiología , Ratones Endogámicos C57BL , Estrés Oxidativo , Especies Reactivas de Oxígeno , Condicionamiento Físico Animal/fisiologíaRESUMEN
Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain. Contrarily to wild-type mice, OCT2-invalidated mice failed to respond to prolonged fluoxetine treatment in a chronic depression model induced by corticosterone exposure recapitulating core symptoms of depression, i.e., anhedonia, social withdrawal, anxiety, and memory impairment. After corticosterone and fluoxetine treatment, the levels of tryptophan and its metabolites serotonin and kynurenine were decreased in the brain of OCT2 mutant mice compared to wild-type mice and reciprocally tryptophan and kynurenine levels were increased in mutants' plasma. OCT2 was detected by immunofluorescence in several structures at the blood-cerebrospinal fluid (CSF) or brain-CSF interface. Tryptophan supplementation during fluoxetine treatment increased brain concentrations of tryptophan and, more discreetly, of 5-HT in wild-type and OCT2 mutant mice. Importantly, tryptophan supplementation improved the sensitivity to fluoxetine treatment of OCT2 mutant mice, impacting chiefly anhedonia and short-term memory. Western blot analysis showed that glycogen synthase kinase-3ß (GSK3ß) and mammalian/mechanistic target of rapamycin (mTOR) intracellular signaling was impaired in OCT2 mutant mice brain after corticosterone and fluoxetine treatment and, conversely, tryptophan supplementation recruited selectively the mTOR protein complex 2. This study provides the first evidence of the physiological relevance of OCT2-mediated tryptophan transport, and its biological consequences on serotonin homeostasis in the brain and SSRI efficacy.
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Trastorno Depresivo Mayor , Transportador 2 de Cátion Orgánico , Inhibidores Selectivos de la Recaptación de Serotonina , Animales , Ratones , Anhedonia , Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Corticosterona/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Fluoxetina/farmacología , Quinurenina/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Triptófano/metabolismoRESUMEN
OBJECTIVES: Intensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so-called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter-regulatory response (CRR). Nevertheless, the VMH receives projections from other brain areas which could participate in the regulation of the CRR. In particular, studies suggest a potential role of the serotonin (5-HT) network. Thus, the objective of this study was to determine the contribution of 5-HT neurons in CRR control. METHODS: Complementary approaches have been used to test this hypothesis in quantifying the level of 5-HT in several brain areas by HPLC in response to insulin-induced hypoglycemia, measuring the electrical activity of dorsal raphe (DR) 5-HT neurons in response to insulin or decreased glucose level by patch-clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the CRR to the modulation of the activity of 5-HT neurons using pharmacological or pharmacogenetic approaches. RESULTS: HPLC measurements show that the 5HIAA/5HT ratio is increased in several brain regions including the VMH in response to insulin-induced hypoglycemia. Patch-clamp electrophysiological recordings show that insulin, but not decreased glucose level, increases the firing frequency of DR 5-HT neurons in the DR. In vivo, both the pharmacological inhibition of 5-HT neurons by intraperitoneal injection of the 5-HT1A receptor agonist 8-OH-DPAT or the chemogenetic inhibition of these neurons reduce glucagon secretion, suggesting an impaired CRR. CONCLUSION: Taken together, these data highlight a new neuronal network involved in the regulation of the CRR. In particular, this study shows that DR 5-HT neurons detect iatrogenic hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.
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Glucagón , Hipoglucemia , Humanos , Neuronas Serotoninérgicas , Serotonina/farmacología , Hipoglucemia/inducido químicamente , Insulina/farmacología , Glucosa , Enfermedad IatrogénicaRESUMEN
Identifying the factors contributing to the etiology of anxiety and depression is critical for the development of more efficacious therapies. Serotonin (5-HT) is intimately linked to both disorders. The inhibitory serotonin-1A (5-HT(1A)) receptor exists in two separate populations with distinct effects on serotonergic signaling: (1) an autoreceptor that limits 5-HT release throughout the brain and (2) a heteroreceptor that mediates inhibitory responses to released 5-HT. Traditional pharmacologic and transgenic strategies have not addressed the distinct roles of these two receptor populations. Here we use a recently developed genetic mouse system to independently manipulate 5-HT(1A) autoreceptor and heteroreceptor populations. We show that 5-HT(1A) autoreceptors act to affect anxiety-like behavior. In contrast, 5-HT(1A) heteroreceptors affect responses to forced swim stress, without effects on anxiety-like behavior. Together with our previously reported work, these results establish distinct roles for the two receptor populations, providing evidence that signaling through endogenous 5-HT(1A) autoreceptors is necessary and sufficient for the establishment of normal anxiety-like behavior.
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Ansiedad/metabolismo , Conducta Animal/fisiología , Red Nerviosa/metabolismo , Neuronas/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Animales , Ansiedad/genética , Ansiedad/fisiopatología , Autorradiografía , Catalepsia , Electrofisiología , Ratones , Ratones Noqueados , Microdiálisis , Red Nerviosa/fisiopatología , Receptor de Serotonina 5-HT1A/genéticaRESUMEN
Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT(1A)) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT(1A) autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT(1A) autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.
Asunto(s)
Autorreceptores/efectos de los fármacos , Corticosterona/administración & dosificación , Fluoxetina/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Resistencia a Medicamentos , Quimioterapia Combinada , Fluoxetina/administración & dosificación , RatonesRESUMEN
A serotonin (5-HT) transporter (5-HTT; SERT) polymorphism has been associated with depressive states and poor responses to selective serotonin reuptake inhibitors (SSRIs). Given the similar attenuation of SERT activity in SERT+/- mice and in humans with short allele(s) of SERT in its promoter region, it is conceivable that SERT+/- mice offer an adequate model to mimic the human subpopulation with respect to their altered response to SSRIs. This study investigated the effects of the most selective SSRI escitalopram, in heterozygous SERT+/- mice using a combined electrophysiological and neurochemical approach. Results indicated that administration of escitalopram for 2 d resulted in a 72% and 63% decrease in dorsal raphe 5-HT neuronal firing rate in SERT+/+ and SERT+/- mice, respectively. In contrast, administration of escitalopram for 21 d produced a gradual recovery of 5-HT neuronal firing rate to basal level in SERT+/+, but not in SERT+/- mice. In the hippocampus, microdialysis revealed that sustained administration of escitalopram produced a greater increase in extracellular 5-HT ([5-HT]ext) outflow in SERT+/- than in the wild-types with or without a washout of the SSRI. Nevertheless, the ability of microiontophoretically applied 5-HT to inhibit the firing rate of CA3 pyramidal neurons was not different between SERT+/+ and SERT+/- mice given escitalopram for 21 d. The data indicate that the poor response to SSRIs of depressive patients with short allele(s) of SERT is not attributable to a lesser increase in 5-HT transmission in the hippocampus.
Asunto(s)
Citalopram/farmacología , Núcleo Dorsal del Rafe/efectos de los fármacos , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Región CA3 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/fisiología , Fármacos del Sistema Nervioso Central/farmacología , Núcleo Dorsal del Rafe/fisiología , Espacio Extracelular/metabolismo , Hipocampo/fisiología , Masculino , Ratones Transgénicos , Neuronas/fisiología , Piperazinas/farmacología , Cloruro de Potasio/farmacología , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Factores de TiempoRESUMEN
Major depression (MD) is one of the most common psychiatric disorders worldwide. Currently, the first-line treatment for MD targets the serotonin system but these drugs, notably the selective serotonin reuptake inhibitors, usually need 4 to 6 weeks before the benefit is felt and a significant proportion of patients shows an unsatisfactory response. Numerous treatments have been developed to circumvent these issues as venlafaxine, a mixed serotonin-norepinephrine reuptake inhibitor that binds and blocks both the SERT and NET transporters. Despite this pharmacological profile, it is difficult to have a valuable insight into its ability to produce more robust efficacy than single-acting agents. In this review, we provide an in-depth characterization of the pharmacological properties of venlafaxine from in vitro data to preclinical and clinical efficacy in depressed patients and animal models of depression to propose an indirect comparison with the most common antidepressants. Preclinical studies show that the antidepressant effect of venlafaxine is often associated with an enhancement of serotonergic neurotransmission at low doses. High doses of venlafaxine, which elicit a concomitant increase in 5-HT and NE tone, is associated with changes in different forms of plasticity in discrete brain areas. In particular, the hippocampus appears to play a crucial role in venlafaxine-mediated antidepressant effects notably by regulating processes such as adult hippocampal neurogenesis or the excitatory/inhibitory balance. Overall, depending on the dose used, venlafaxine shows a high efficacy on depressive-like symptoms in relevant animal models but to the same extent as common antidepressants. However, these data are counterbalanced by a lower tolerance. In conclusion, venlafaxine appears to be one of the most effective treatments for treatment of major depression. Still, direct comparative studies are warranted to provide definitive conclusions about its superiority.
Asunto(s)
Trastorno Depresivo Mayor , Serotonina , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ciclohexanoles/farmacología , Ciclohexanoles/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Clorhidrato de Venlafaxina/farmacología , Clorhidrato de Venlafaxina/uso terapéuticoRESUMEN
Triple reuptake inhibitors represent a potential new class of antidepressant drugs that block norepinephrine (NE), dopamine (DA) and serotonin [5-hydroxytryptamine (5-HT)] transporters. The present in-vivo electrophysiological study was undertaken to determine the effects of the triple reuptake inhibitors SEP-225289 and DOV216303 on the neuronal activities of locus coeruleus (LC) NE, ventral tegmental area (VTA) DA and dorsal raphe (DR) 5-HT neurons. Administered acutely, SEP-225289 and DOV216303 dose-dependently decreased the spontaneous firing rate of LC NE, VTA DA and DR 5-HT neurons through the activation of α2, D2 and 5-HT(1A) autoreceptors, respectively. Both compounds predominantly inhibited the firing rate of LC NE neurons while producing only a partial decrease in VTA DA and DR 5-HT neuronal discharge. SEP-225289 was equipotent at inhibiting 5-HT and NE transporters since it prolonged to the same extent the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the inhibition induced by microiontophoretic application of 5-HT and NE. Finally, in the presence of WAY100635, a 5-HT(1A) receptor antagonist, SEP-225289 activated 5-HT neurons at doses that normally did not inhibit them. Taken together, the present results indicate that reciprocal interactions among NE, DA and 5-HT inputs need to be considered to anticipate the net effect of triple reuptake inhibitors on the enhancement of brain monoamine transmission. The results also suggest that the therapeutic action of triple reuptake inhibitors may be potentiated by antagonizing the cell body 5-HT(1A) autoreceptors.
Asunto(s)
Antagonistas Adrenérgicos/farmacología , Aminas/farmacología , Compuestos Aza/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ciclobutanos/farmacología , Antagonistas de Dopamina/farmacología , Fenómenos Electrofisiológicos/efectos de los fármacos , Neuronas/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Antidepresivos/farmacología , Dopamina/metabolismo , Evaluación Preclínica de Medicamentos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Masculino , Neuronas/metabolismo , Norepinefrina/metabolismo , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/fisiología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
Astrocytes were traditionally regarded as cells important to neuronal activity, providing both metabolic and structural supports. Recent evidence suggests that they may also play a crucial role in the control of higher brain functions. In keeping with this hypothesis, it is now well accepted that astrocytes contribute to stress but also react to antidepressant drugs as they express serotonergic transporters and receptors. However, the downstream mechanisms leading to the fine-tuned regulation of mood are still unknown. This chapter pays attention to the role of astrocytes in the regulation of emotional behavior and related serotonergic neurotransmission. In particular, it gives a current state of the clinical and preclinical evidence showing that astrocytes respond to environmental conditions and antidepressant drugs through the release of gliotransmitters and neurotrophic factors which in turn, influence serotonergic tone in discrete brain areas. This state-of-the-art review aims at demonstrating the remarkable potential for novel therapeutic antidepressant strategies targeting these glial cells.