RESUMEN
Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.
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Psilocibina , Psilocibina/uso terapéutico , Psilocibina/farmacología , Humanos , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h post-treatment. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than anxiolytic effects.
RESUMEN
Depression is a common psychiatric disorder affecting around 300 million people worldwide. Serum cortisol and glucocorticoid levels in humans are reportedly higher in patients with depression compared to controls. Furthermore, rodents repeatedly treated with exogenous corticosterone (CORT), a glucocorticoid in rodents, exhibit deficits in emotional behaviors. To confirm the availability of mice with chronic CORT treatment as an animal model of depression, we investigated the effect of chronic CORT treatment on depression-like behavioral and neuropathological phenotypes in C57BL/6N male mice. Behavioral studies showed depression- and anxiety-like behaviors in mice treated with CORT compared with control mice in the forced-swim and elevated-plus maze tests. Additionally, treated mice represented anhedonia and social behavior impairments in the sucrose preference and social interaction tests, respectively. Brains of depression patients have altered expression of reelin, an extracellular matrix protein involved in neuronal development and function. Likewise, in the present study, mice with chronic CORT treatment also exhibited reelin downregulation in cells of the hippocampus. Hence, we investigated therapeutic effects of reelin supplementation on CORT-induced behavioral abnormalities in mice. Microinjections of recombinant reelin protein into the hippocampus did not rescue behavioral deficits in mice with chronic CORT treatment. These results suggest that C57BL/6N male mice chronically treated with CORT are a suitable animal depression model, in which depressive behaviors may occur independently of the alternation of hippocampal Reelin expression.
Asunto(s)
Corticosterona , Glucocorticoides , Humanos , Masculino , Ratones , Animales , Glucocorticoides/metabolismo , Glucocorticoides/farmacología , Ratones Endogámicos C57BL , Hipocampo/metabolismo , Emociones , Depresión/metabolismo , Ratones Endogámicos , Conducta Animal , Modelos Animales de EnfermedadRESUMEN
Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT 2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic-and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice 24 h post-treatment. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than an anxiolytic effects.
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Major depressive disorder presents a substantial global health burden, and at least 30-40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a "breakthrough therapy approach" for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the "psychedelic renaissance". Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HT2A receptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and "mystical experience" that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target.
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Trastorno Depresivo Mayor , Alucinógenos , Ketamina , Humanos , Alucinógenos/efectos adversos , Psilocibina/farmacología , Psilocibina/uso terapéutico , Serotonina , Ketamina/farmacología , Ketamina/uso terapéutico , Receptor de Serotonina 5-HT2A , Trastorno Depresivo Mayor/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Alucinaciones/inducido químicamente , Alucinaciones/tratamiento farmacológicoRESUMEN
The serotonergic and glutamatergic neurotransmitter systems have been implicated in the pathophysiology of schizophrenia, and increasing evidence shows that they interact functionally. Of note, the Gq/11-coupled serotonin 5-HT2A (5-HT2A) and the Gi/o-coupled metabotropic glutamate type 2 (mGlu2) receptors have been demonstrated to assemble into a functional heteromeric complex that modulates the function of each individual receptor. For conformation of the heteromeric complex, corresponding transmembrane-4 segment of 5-HT2A and mGlu2 are required. The 5-HT2A/mGlu2 heteromeric complex is necessary for the activation of Gq/11 proteins and for the subsequent increase in the levels of the intracellular messenger Ca2+. Furthermore, signaling via the heteromeric complex is dysregulated in the post-mortem brains of patients with schizophrenia, and could be linked to altered cortical function. From a behavioral perspective, this complex contributes to the hallucinatory and antipsychotic behaviors associated with 5-HT2A and mGlu2/3 agonists, respectively. Synaptic and epigenetic mechanisms have also been found to be significantly associated with the mGlu2/5-HT2A heteromeric complex. This review summarizes the role of crosstalk between mGlu2 and 5-HT2A in the mechanism of antipsychotic effects and introduces recent key advancements on this topic.
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Antipsicóticos , Receptores de Glutamato Metabotrópico , Esquizofrenia , Humanos , Antipsicóticos/farmacología , Serotonina , Ácido Glutámico/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Agonistas de Aminoácidos Excitadores , Receptor de Serotonina 5-HT2ARESUMEN
Long-term exposure to physical and/or psychosocial stress during early life and/or adolescence increases the risk of psychiatric disorders such as major depressive disorder and anxiety disorders. However, the molecular mechanisms underlying early stress-induced brain dysfunction are poorly understood. In the present study, mice at 4 weeks old were subjected to chronic mild unpredictable stress (CMUS) for 4 weeks, and subsequently to assays of emotion-related behaviors. Thereafter, they were sacrificed and their brains were collected for real-time quantitative polymerase chain reaction (RT-qPCR). Mice with CMUS during adolescence showed despair behavior, anxiety-like behavior, social behavior deficits, and anhedonia in forced-swim, marble-burying, social interaction, and sucrose preference tests, respectively. Additionally, RT-qPCR revealed that the expression levels of sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates stress responses, were down-regulated in the prefrontal cortex and hippocampus of mice with CMUS compared with control mice. Next, to investigate the pathophysiological role of decreased Sirt1 expression levels in stress-induced behavioral deficits, we assessed the effects of resveratrol, a pharmacological activator of SIRT1, in mice exposed to CMUS. Chronic treatment with resveratrol prevented CMUS-induced social behavior deficits and depression-like behaviors. These results suggest that CMUS during adolescence decreases Sirt1 expression in the brain, leading to deficits in emotional behavior. Accordingly, SIRT1 activators, such as resveratrol, may be preventive agents against abnormalities in emotional behavior following stress during an immature period.
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Trastorno Depresivo Mayor , Sirtuina 1 , Animales , Ratones , Conducta Animal , Depresión/psicología , Trastorno Depresivo Mayor/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Resveratrol , Sirtuina 1/metabolismo , Estrés Psicológico/metabolismo , EmocionesRESUMEN
In the pathophysiology of Alzheimer's disease, the deposition of amyloid ß peptide (Aß) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. We have already reported that betaine (glycine betaine), an osmolyte and methyl donor in cells, prevents the development of cognitive impairment in mice with intracerebroventricular injection of Aß25-35, an active fragment of Aß, associated with oxidative stress in the hippocampus, but molecular mechanisms of betaine remain to be determined. Here, to investigate a key molecule underlying the preventive effect of betaine against cognitive impairments in Aß25-35-injected mice, cognitive tests and qPCR assays were performed in Aß25-35-injected mice with continuous betaine intake, in which intake was started a day before Aß25-35 injection, and then continued for 8 days. The Aß25-35 injection impaired short-term and object recognition memories in the Y-maze and object recognition tests, respectively. PCR assays revealed the down-regulation of Sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates metabolic responses, in the hippocampus of Aß25-35-injected mice, whereas betaine intake prevented memory deficits as well as the decrease of hippocampal SIRT1 expression in Aß25-35-injected mice. Further, sirtinol, an inhibitor of the Sirtuin family, blocked the preventive effect of betaine against memory deficits. On the other hand, resveratrol, the potent compound that activates SIRT1, also prevented memory impairments in Aß25-35-injected mice, suggesting that SIRT1 plays a causative role in the preventive effect of betaine against memory deficits caused by Aß exposure.
Asunto(s)
Enfermedad de Alzheimer , Betaína , Disfunción Cognitiva , Sirtuina 1 , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Animales , Betaína/uso terapéutico , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Aprendizaje por Laberinto , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Ratones , Fragmentos de Péptidos/metabolismo , Sirtuina 1/metabolismoRESUMEN
BACKGROUND: The deposition of amyloid-ß (Aß) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer's disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aß, whereas the effect of betaine in chronic models of AD remains unknown. OBJECTIVE: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a genetic AD model. METHODS: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. RESULTS: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. CONCLUSION: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity.
Asunto(s)
Betaína , Disfunción Cognitiva/prevención & control , Modelos Animales de Enfermedad , Fármacos Gastrointestinales , Expresión Génica , Hipocampo/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Betaína/metabolismo , Betaína/farmacología , Cognición , Fármacos Gastrointestinales/metabolismo , Fármacos Gastrointestinales/farmacología , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sinapsis/metabolismoRESUMEN
In the majority of schizophrenia patients, chronic atypical antipsychotic administration produces a significant reduction in or even complete remission of psychotic symptoms such as hallucinations and delusions. However, these drugs are not effective in improving cognitive and emotional deficits in patients with schizophrenia. Atypical antipsychotic drugs have a high affinity for the dopamine D2 receptor, and a modest affinity for the serotonin 5-HT2A receptor. The cognitive and emotional deficits in schizophrenia are thought to involve neural networks beyond the classical dopaminergic mesolimbic pathway, however, including serotonergic systems. For example, mutations in the RELN gene, which encodes Reelin, an extracellular matrix protein involved in neural development and synaptic plasticity, are associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Furthermore, hippocampal Reelin levels are down-regulated in the brains of both schizophrenic patients and in rodent models of schizophrenia. In the present study, we investigated the effect of Reelin microinjection into the mouse hippocampus on behavioral phenotypes to evaluate the role of Reelin in neurodevelopmental disorders and to test a therapeutic approach that extends beyond classical monoamine targets. To model the cognitive and emotional deficits, as well as histological decreases in Reelin-positive cell numbers and hippocampal synaptoporin distribution, a synaptic vesicle protein, offspring that were prenatally exposed to maternal immune activation were used. Microinjections of recombinant Reelin protein into the hippocampus rescued impairments in object memory and anxiety-like behavior and recruited synaptoporin in the hippocampus in offspring exposed to antenatal inflammation. These results suggest that Reelin supplementation has the potential to treat cognitive and emotional impairments, as well as synaptic disturbances, in patients with neurodevelopmental disorders such as schizophrenia.
RESUMEN
Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.
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Conducta Animal , Susceptibilidad a Enfermedades , Microbioma Gastrointestinal , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/psicología , Problema de Conducta , Maduración Sexual , Factores de Edad , Animales , Antibacterianos/administración & dosificación , Modelos Animales de Enfermedad , Memoria , Ratones , Fenotipo , Reconocimiento en Psicología , Esquizofrenia/etiologíaRESUMEN
Sodium valproate (VPA) is the most widely used antiepileptic drug and is increasingly also being used for several non-epileptic indications including migraines and bipolar disorder. It is known that maternal VPA exposure during pregnancy increases the risk of autism spectrum disorder (ASD) in children. Animal model studies have shown that maternal treatment with VPA in rodents conveys an increased risk for ASD-like phenotypes at the molecular, cellular, and behavioral levels. In contrast, the effect of paternal VPA exposure on behaviors in offspring is unknown. This study seeks to investigate whether paternal VPA exposure in rodents triggers behavioral and epigenetic alterations in offspring. The results show that paternal VPA exposure impairs object cognitive memory, suppresses the hyperactivity evoked by an NMDA receptor antagonist in male and female offspring, and disturbs sensorimotor gating in only females. In addition, since VPA is well known as an inhibitor of histone deacetylases, we examined the levels of acetylated histone H3 in the frontal cortex and hippocampus in the offspring of VPA-exposed sires. Interestingly, paternal VPA exposure down-regulates the levels of acetylated histone H3 in the brain in offspring even though VPA exposure increased acetylated histone H3 levels in the testes of sires. Collectively, these findings suggest that paternal VPA exposure may disturb the histone acetylation balance in the brain of offspring through changes in the germline epigenome, leading to behavioral alterations in offspring.
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Anticonvulsivantes/toxicidad , Conducta Animal/efectos de los fármacos , Exposición Paterna/efectos adversos , Ácido Valproico/toxicidad , Animales , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Trastorno por Déficit de Atención con Hiperactividad/psicología , Química Encefálica/efectos de los fármacos , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/metabolismo , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Filtrado Sensorial/efectos de los fármacos , Caracteres Sexuales , Conducta SocialRESUMEN
Following the publication of this article Figs. 3b, c were published incorrectly. Also in sub-panel c of Fig. 4, 'Chronic cloza ine' should read 'Chronic clozapine'.
RESUMEN
In the pathophysiology of Alzheimer's disease (AD), the deposition of amyloid ß protein (Aß) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. Betaine (glycine betaine or trimethylglycine), known as an osmolyte and methyl donor in mammalian cells, has been reported to suppress the proinflammatory response and oxidative stress in the kidneys, but the effects of betaine on brain diseases remain to be determined. Here, to investigate the effects of betaine treatment on cognitive impairment and the increase in oxidative stress in the brain of an AD animal model, we performed a novel object recognition test and measured the malondialdehyde (MDA; a marker of oxidative stress) levels in the frontal cortex and hippocampus of mice intracerebroventricularly injected with Aß25-35, an active fragment of Aß. Betaine prevented cognitive impairment as well as increases of the cortical and hippocampal MDA levels in Aß25-35-injected mice. Of note, NNC 05-2090, a selective inhibitor of betaine/GABA transporter-1 (GAT2/BGT-1), reduced the preventive effects of betaine on Aß25-35-induced cognitive impairment without affecting the increased MDA levels in the brain of Aß25-35-injected mice. As betaine is used as a substrate of GAT2/BGT-1, these results suggest that betaine is transported through GAT2/BGT-1 and prevents cognitive impairment in Aß25-35-injected mice, but GAT2/BGT-1 function is not required for the antioxidant effects of betaine.
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Péptidos beta-Amiloides/toxicidad , Betaína/farmacología , Encéfalo/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/prevención & control , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Inyecciones , Masculino , Malondialdehído/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiologíaRESUMEN
Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration occurred in association with HDAC2-dependent repressive histone modifications at the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.
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Antipsicóticos/farmacología , Clozapina/farmacología , Lóbulo Frontal/efectos de los fármacos , Histona Desacetilasa 2/metabolismo , Trastornos Psicóticos/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Animales , Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Modelos Animales de Enfermedad , Lóbulo Frontal/metabolismo , Histona Desacetilasa 2/genética , Ratones , Ratones Noqueados , Trastornos Psicóticos/tratamiento farmacológico , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
BACKGROUND: Polyriboinosinic-polyribocytidylic acid (polyI:C) triggers a strong innate immune response that mimics immune activation by viral infections. Induction of interferon-induced transmembrane protein 3 (Ifitm3) in astrocytes has a crucial role in polyI:C-induced neurodevelopmental abnormalities. Through a quantitative proteomic screen, we previously identified candidate astroglial factors, such as matrix metalloproteinase-3 (Mmp3) and follistatin-like 1 (Fstl1), in polyl:C-induced neurodevelopmental impairment. Here, we characterized the Ifitm3-dependent inflammatory processes focusing on astrocyte-derived Fstl1 following polyI:C treatment to assess the neuropathologic role of Fstl1. METHODS: Astrocytes were treated with PBS (control) or polyI:C (10 µg/mL). The conditioned medium was collected 24 h after the polyI:C treatment and used as astrocyte condition medium (ACM). The expression of Fstl1 mRNA and extracellular Fstl1 protein levels were analyzed by quantitative PCR and western blotting, respectively. For functional studies, neurons were treated with ACM and the effects of ACM on dendritic elongation were assayed. To examine the role of Fstl1, recombinant Fstl1 protein and siRNA for Fstl1 were used. To investigate the expression of Fstl1 in vivo, neonatal mice were treated with vehicle or polyI:C on postnatal day 2 to 6. RESULTS: ACM prepared with polyI:C (polyI:C ACM) contained significantly higher Fstl1 protein than control ACM, but no increase in Fstl1 was observed in polyI:C ACM derived from Ifitm3-deficient astrocytes. We found that the production of Fstl1 involves the inflammatory responsive molecule Ifitm3 in astrocytes and influences neuronal differentiation. In agreement, the levels of Fstl1 increased in the hippocampus of polyI:C-treated neonatal mice. COS7 cells co-transfected with both Fstl1 and Ifitm3 had higher extracellular levels of Fstl1 than the cells transfected with Fstl1 alone. Treatment of primary cultured hippocampal neurons with recombinant Fstl1 impaired dendritic elongation, and the deleterious effect of polyI:C ACM on dendritic elongation was attenuated by knockdown of Fstl1 in astrocytes. CONCLUSIONS: The extracellular level of Fstl1 is regulated by Ifitm3 in astrocytes, which could be involved in polyI:C-induced neurodevelopmental impairment.
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Astrocitos/efectos de los fármacos , Proteínas Relacionadas con la Folistatina/metabolismo , Inmunidad Innata/fisiología , Proteínas de la Membrana/metabolismo , Regulación hacia Arriba/fisiología , Animales , Animales Recién Nacidos , Astrocitos/química , Encéfalo/citología , Antígeno CD11b/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/farmacología , Dendritas/efectos de los fármacos , Embrión de Mamíferos , Proteínas Relacionadas con la Folistatina/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunidad Innata/efectos de los fármacos , Metaloproteinasa 3 de la Matriz/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Poli I-C/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings suggested that upregulation of histone deacetylase 2 (HDAC2) expression upon chronic antipsychotic treatment may lead to negative effects on cognition and cortical synaptic structure. Here we tested different phenotypes of psychosis, synaptic plasticity, cognition and antipsychotic drug action in HDAC2 conditional knockout (HDAC2-cKO) mice and controls. Conditional depletion of HDAC2 function in glutamatergic pyramidal neurons led to a protective phenotype against behavior models induced by psychedelic and dissociative drugs, such as DOI and MK801, respectively. Immunoreactivity toward synaptophysin, which labels presynaptic terminals of functional synapses, was decreased in the frontal cortex of control mice chronically treated with clozapine - an opposite effect occurred in HDAC2-cKO mice. Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.
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Antipsicóticos/farmacología , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Vorinostat/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Cognición/efectos de los fármacos , Cognición/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glutámico/metabolismo , Histona Desacetilasa 2/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Psicosis Inducidas por Sustancias/psicología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/patología , Distribución Aleatoria , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
People preferably take zero or low-calorie beverages and foods with artificial sweeteners even though it has been recently suggested that long-term artificial sweetener use affects physiological functions. In addition, a lower body weight was considered to be more healthful, but an abnormally low body weight caused by an excessive diet has been reported to cause health problems. Acesulfame potassium (AceK) is one of the most commonly used for foods and beverages because of its resistance to thermal degradation and marked sweetness. However, the combined effect of AceK and a low body weight on the physiological functions remains unknown. Here, we investigated the effect of long-term AceK fluid intake on the cognitive function under dietary restriction. We administered AceK to mice fed a low carbohydrate (LC) diet for 4â¯weeks, and behavioral assays were then performed for a week. The mice fed the LC diet with AceK treatment for 4â¯weeks showed an increase in water intake and a decrease in short-term and object cognitive memories in the Y-maze and novel object recognition tests, respectively. Mice were sacrificed after behavioral tests to measure glucose levels. The glucose levels in the frontal cortex were significantly decreased in mice fed the LC diet with AceK treatment in comparison with mice fed the LC diet alone, although there was no significant difference in the plasma glucose levels. These results suggest that the combination of long-term AceK intake and the LC diet affects the cognitive function through the reduction of cortical glucose levels.
Asunto(s)
Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Dieta Baja en Carbohidratos/efectos adversos , Edulcorantes/administración & dosificación , Tiazinas/administración & dosificación , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , ARN Mensajero/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Factores de TiempoRESUMEN
Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.