RESUMO

Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.

Assuntos

Núcleo Accumbens , Ratos Wistar , Privação do Sono , Área Tegmentar Ventral , Animais , Masculino , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Ratos , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Receptor A2A de Adenosina/metabolismo , Hiperalgesia/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos dos fármacos , Locus Cerúleo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Carragenina , Receptores de GABA-A/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia

RESUMO

The neuroendocrine system of crustaceans is complex and regulates many processes, such as development, growth, reproduction, osmoregulation, behavior, and metabolism. Once stimulated, crustaceans' neuroendocrine tissues modulate the release of monoamines, ecdysteroids, and neuropeptides that can act as hormones or neurotransmitters. Over a few decades, research has unraveled some mechanisms governing these processes, substantially contributing to understanding crustacean physiology. More aspects of crustacean neuroendocrinology are being comprehended with molecular biology, transcriptome, and genomics analyses. Hence, these studies will also significantly enhance the ability to cultivate decapods, such as crabs and shrimps, used as human food sources. In this review, current knowledge on crustacean endocrinology is updated with new findings about crustacean hormones, focusing mainly on the main neuroendocrine organs and their hormones and the effects of these molecules regulating metabolism, growth, reproduction, and color adaptation. New evidence about vertebrate-type hormones found in crustaceans is included and discussed. Finally, this review may assist in understanding how the emerging chemicals of environmental concern can potentially impair and disrupt crustacean's endocrine functions and their physiology.

Assuntos

Crustáceos , Sistemas Neurossecretores , Animais , Crustáceos/fisiologia , Crustáceos/metabolismo , Neuropeptídeos/metabolismo , Sistemas Neurossecretores/fisiologia , Sistemas Neurossecretores/metabolismo , Reprodução/fisiologia

RESUMO

Persistent pain conditions and sleep disorders are public health problems worldwide. It is widely accepted that sleep disruption increases pain sensitivity; however, the underlying mechanisms are poorly understood. In this study, we used a protocol of 6 hours a day of total sleep deprivation for 3 days in rats to advance the understanding of these mechanisms. We focused on gender differences and the dopaminergic mesocorticolimbic system. The findings demonstrated that sleep restriction (SR) increased pain sensitivity in a similar way in males and females, without inducing a significant stress response. This pronociceptive effect depends on a nucleus accumbens (NAc) neuronal ensemble recruited during SR and on the integrity of the anterior cingulate cortex (ACC). Data on indirect dopaminergic parameters, dopamine transporter glycosylation, and dopamine and cyclic adenosine monophosphate (AMP)-regulated phosphoprotein-32 phosphorylation, as well as dopamine, serotonin, and norepinephrine levels, suggest that dopaminergic function decreases in the NAc and ACC after SR. Complementarily, pharmacological activation of dopamine D2, but not D1 receptors either in the ACC or in the NAc prevents SR from increasing pain sensitivity. The ACC and NAc are the main targets of dopaminergic mesocorticolimbic projections with a key role in pain modulation. This study showed their integrative role in the pronociceptive effect of SR, pointing to dopamine D2 receptors as a potential target for pain management in patients with sleep disorders. These findings narrow the focus of future studies on the mechanisms by which sleep impairment increases pain sensitivity. PERSPECTIVE: This study demonstrates that the pronociceptive effect of SR affects similarly males and females and depends on a NAc neuronal ensemble recruited during SR and on the integrity of the ACC. Findings on dopaminergic function support dopamine D2 receptors as targets for pain management in sleep disorders patients.

Assuntos

Dopamina , Núcleo Accumbens , Humanos , Masculino , Ratos , Animais , Núcleo Accumbens/fisiologia , Dopamina/farmacologia , Giro do Cíngulo , Dor , Privação do Sono/complicações

RESUMO

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.

Assuntos

Metilfenidato , Humanos , Criança , Ratos , Animais , Idoso , Metilfenidato/farmacologia , Serotonina/farmacologia , Área Tegmentar Ventral , Dopamina/farmacologia , Núcleo Dorsal da Rafe , Locus Cerúleo , Norepinefrina/farmacologia , Ratos Sprague-Dawley

RESUMO

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

RESUMO

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

Assuntos

Transtornos Heredodegenerativos do Sistema Nervoso , Doença de Huntington , Animais , Camundongos , Doença de Huntington/genética , Doença de Huntington/terapia , Aminas , Proliferação de Células , Terapia Combinada

RESUMO

Drosophila melanogaster is a model organism to study molecular mechanisms and the role of the genes and proteins involved in thermal nociception. Monoamines (i.e. dopamine) have been involved in temperature preference behavior in D. melanogaster. Therefore, we investigated whether the monoamines, particularly dopamine and serotonin, participate in the response to thermal nociceptive stimuli in D. melanogaster. Flies were treated with reserpine (an inhibitor of vesicular monoamines transporter, 3-300 µM), 3-Iodo-L-tyrosine (3-I-T, an inhibitor of tyrosine hydroxylase, 16.28-65.13 mM), and para-Chloro-DL-phenylalanine (PCPA, an inhibitor of tryptophan hydroxylase, 20-80 mM); then, the flies were subjected to tests of thermal tolerance and avoidance of noxious heat. Climbing behavior was used as a test to evaluate locomotor activity. Reserpine reduces the thermal tolerance profile of the D. melanogaster, as well as the avoidance of noxious heat and locomotor activity depending on the concentration. PCPA, but not 3-I-T, decreased heat tolerance and avoidance of noxious heat. These data suggest that monoamines, particularly serotonin, are associated with the impaired avoidance of noxious heat which could be related to the reduction of heat tolerance in D. melanogaster.

Assuntos

Drosophila melanogaster , Termotolerância , Animais , Drosophila melanogaster/metabolismo , Dopamina/metabolismo , Reserpina , Serotonina/metabolismo

RESUMO

La depresión es una de las patologías más abordadas actualmente, la presencia de síntomas característicos provoca gran precaución y requiere de alto cuidado personal, además, el padecimiento de esta enfermedad se enlaza directamente a los aspectos neurobiológicos que explica los procesos dentro del sistema nervioso central. Objetivo. El objetivo del presente estudio es describir las siguientes teorías de la neurología de la depresión mayor: teoría de la monoaminas, teoría neurotrófica y teoría inflamatoria junto con su relación con la depresión. Metodología. Se realizó una revisión bibliográfica de la literatura científica relacionados a la neurobiología de la depresión mayor, incluyendo estudios; experimentales, originales, metaanálisis y paginas oficiales. Se utilizó la base de datos PubMed, y Google scholar, cuyos documentos fueron publicados entre 2015 a 2022 en idioma español e inglés; se utilizaron los términos MESH y DeCs: "depresión" "inflamación" "neurobiología" "monoaminas biogénicas". Conclusión: Se concluye que, a pesar de los nuevos descubrimientos en cuanto a diferentes mecanismos de la neurobiología de la depresión, aún existen vacíos por descubrir que impiden desarrollar una teoría unificada de la etiología.

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Depression is currently one of the most frequently addressed pathologies, the presence of characteristic symptoms causes great caution and requires high personal care, in addition, the suffering of this disease is directly linked to the neurobiological aspects that explain the processes within the central nervous system. Objective. The aim of the present study is to describe the following theories of the neurology of major depression: monoamine theory, neurotrophic theory and inflammatory theory together with their relation to depression. Methodology. A bibliographic review of the scientific literature related to the neurobiology of major depression was carried out, including experimental studies, original studies, meta-analysis and official pages. The PubMed database was used, and Google scholar, whose documents were published between 2015 to 2022 in Spanish and English language; the terms MESH and DeCs were used: "depression" "inflammation" "neurobiology" "biogenic monoamines". Conclusion: It is concluded that, despite new discoveries regarding different mechanisms of the neurobiology of depression, there are still undiscovered gaps that prevent the development of a unified theory of etiology.

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A depressão é uma das patologias mais freqüentemente abordadas atualmente, a presença de sintomas característicos causa grande cautela e requer um alto cuidado pessoal, além disso, o sofrimento desta doença está diretamente ligado aos aspectos neurobiológicos que explicam os processos dentro do sistema nervoso central. Objetivo. O objetivo do presente estudo é descrever as seguintes teorias da neurologia da depressão grave: teoria monoamina, teoria neurotrófica e teoria inflamatória, juntamente com sua relação com a depressão. Metodologia. Foi realizada uma revisão bibliográfica da literatura científica relacionada à neurobiologia da depressão grave, incluindo estudos experimentais, estudos originais, meta-análises e páginas oficiais. Utilizamos o banco de dados PubMed e Google scholar, cujos documentos foram publicados entre 2015 e 2022 em espanhol e inglês; usamos os termos MESH e DeCs: "depressão" "inflamação" "neurobiologia" "monoaminas biogênicas". Conclusão: Conclui-se que, apesar das novas descobertas sobre diferentes mecanismos da neurobiologia da depressão, ainda existem lacunas ainda não descobertas que impedem o desenvolvimento de uma teoria unificada da etiologia.

Assuntos

Depressão

RESUMO

Modafinil (MOD) is a wakefulness promoter used to treat sleep disorders such as narcolepsy and obstructive sleep apnea. Its action mechanism consists in inhibiting dopamine (DAT) and norepinephrine (NET) transporters, but it has no affinity for the serotonin transporter (SERT). Modafinil's addictive potential is not yet clear, but one feature that differentiates it from potentially addictive drugs like cocaine revolves around affinity for SERT. The aims of the present study were to determine whether co-administration of MOD with the selective serotonin reuptake inhibitor citalopram (CIT) can increase MOD's psychostimulant effects on motor activity (MA), verify the effects of subsequent self-administration of MOD mixed with CIT, and document the presence of any symptoms of withdrawal. At 60 postnatal days (PD), male Wistar rats were treated chronically (16 days) with MOD at 30 or 60 mg/kg, with MOD+CIT at four dosage combinations administered to four groups (30MOD + CIT3, 30MOD + CIT5, 60MOD + CIT3, 60MOD + CIT5 mg/kg), or with a vehicle. After 40 min of daily drug administration, MA was measured on the open field test. MA increased only in the 60MOD group. The rats co-administered with 30MOD + 3CIT and 60MOD + 3CIT showed a decrease in the motivation to seek a pleasurable stimulus (lower consumption of sweet solution) after treatment concluded. The 60MOD and 60MOD + 3CIT groups showed MA sensitization after MOD intake. Additionally, higher self-administration of the mixture was observed in the groups pre-treated with 30MOD + 3CIT and 60MOD + 3CIT. Results suggest that serotonergic activity enhances modafinil's psychostimulant effects.

Assuntos

Estimulantes do Sistema Nervoso Central , Citalopram , Animais , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Citalopram/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Masculino , Modafinila/farmacologia , Ratos , Ratos Wistar , Proteínas da Membrana Plasmática de Transporte de Serotonina

RESUMO

Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the general population. In mental disorders, the activation of inflammatory pathways in the brain is a major producer of excitotoxicity and an inducer of oxidative stress. The occurrence of these 2 events is partly responsible for the neuronal damage inherent in patients with mental disorders. In the case of MDD, the release of hormone and increase in pro-inflammatory cytokines in plasma and indicators of oxidative stress have been identified as consequences of this event. The most important affectations in patients with MDD are changes in their cognitive and executive functions due to brain inflammation. Hence, these biomarkers can serve as diagnostic and severity classification tools and treatment. In this work, we described the communication pathway between the immune and neuroendocrine systems in MDD and suggested possible therapeutic options for the disease.

Assuntos

Transtorno Depressivo Maior/imunologia , Doenças Neuroinflamatórias/imunologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Sistema Imunitário/metabolismo , Estresse Oxidativo

RESUMO

The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer's disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.

RESUMO

The first third of incubation is critical for embryonic development, and environmental changes during this phase can affect the physiology and survival of the embryos. We evaluated the effects of low (LT), control (CT), and high (HT) temperatures during the first 5 days of incubation on ventilation ( V . E ), body temperature (Tb), oxygen consumption ( V . O2), respiratory equivalent ( V . E / V . O2), and brain monoamines on 3-days-old (3d) and 14-days-old (14d) male and female chickens. The body mass of LT animals of both ages and sexes was higher compared to HT and CT animals (except for 3d males). The heart mass of 14d HT animals was higher than that of CT animals. Thermal manipulation did not affect V . E , V . O2 or V . E / V . O2 of 3d animals in normoxia, except for 3d LT males V . E , which was lower than CT. Regarding 14d animals, the HT females showed a decrease in V . E and V . O2 compared to CT and LT groups, while the HT males displayed a lower V . O2 compared to CT males, but no changes in V . E / V . O2. Both sexes of 14d HT chickens presented a greater Tb compared to CT animals. Thermal manipulations increased the dopamine turnover in the brainstem of 3d females. No differences were observed in ventilatory and metabolic parameters in the 3d animals of either sexes, and 14d males under 7% CO2. The hypercapnic hyperventilation was attenuated in the 14d HT females due to changes in V . O2, without alterations in V . E . The 14d LT males showed a lower V . E , during hypercapnia, compared to CT, without changes in V . O2, resulting in an attenuation in V . E / V . O2. During hypoxia, 3d LT females showed an attenuated hyperventilation, modulated by a higher V . O2. In 14d LT and HT females, the increase in V . E was greater and the hypometabolic response was attenuated, compared to CT females, which resulted in no change in the V . E / V . O2. In conclusion, thermal manipulations affect hypercapnia-induced hyperventilation more so than hypoxic challenge, and at both ages, females are more affected by thermal manipulation than males.

RESUMO

Δ9-tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females.

Assuntos

Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Canabidiol/farmacologia , Dopamina/metabolismo , Dronabinol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Serotonina/metabolismo , Animais , Ansiedade , Feminino , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Caracteres Sexuais , Fatores Sexuais

RESUMO

Stress is crucially related to the pathophysiology of mood disorders, including depression. Since the effectiveness and number of the current pharmacological options still presents significant limitations, research on new substances is paramount. In rodents, several findings have indicated that corticosterone administration induces the manifestation of behavioral and neurochemical aspects of depression. Recently, riparin III has shown antidepressant-like properties in trials performed on animal models. Thus, our goal was to investigate the effects of riparin III on behavioral tests, monoamines levels, oxidative stress and cytokines levels in chronic corticosterone-induced model of depression. To do this, female swiss mice were treated with subcutaneous administration of corticosterone for 22 days. In addition, for the last 10 days, riparin III or fluvoxamine were also administered per os in specific test groups. Control groups received subcutaneous saline injections or distilled water per os. At the end of the timeline, the animals were killed and their hippocampi, prefrontal cortex, and striatum dissected for neurochemical analysis. Brain changes following corticosterone administration were confirmed, and riparin III could reversed the most abnormal behavioral and neurochemical corticosterone-induced alterations. These results suggest the potential antioxidant, anti-inflammatory and antidepressant effects of riparin III after a chronic stress exposure.

Assuntos

Depressão , Preparações Farmacêuticas , Animais , Comportamento Animal , Benzamidas , Corticosterona , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Camundongos , Tiramina/análogos & derivados

RESUMO

Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 µmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities.

Assuntos

Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Neurotransmissores/farmacologia , Piperazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Monoaminas Biogênicas/agonistas , Monoaminas Biogênicas/antagonistas & inibidores , Modelos Animais de Doenças , Masculino , Camundongos , Neurotransmissores/administração & dosagem , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos

RESUMO

Recent evidence suggests that young rodents submitted to high fructose (FRU) diet develop metabolic, and cognitive dysfunctions. However, it remains unclear whether these detrimental effects of FRU intake can also be observed in middle-aged mice. Nine months-old C57BL/6 female mice were fed with water (Control) or 10% FRU in drinking water during 12 weeks. After that, metabolic, and neurochemical alterations were evaluated, focusing on neurotransmitters, and antioxidant defenses. Behavioral parameters related to motor activity, memory, anxiety, and depression were also evaluated. Mice consuming FRU diet displayed increased water, and caloric intake, resulting in weight gain, which was partially compensated due to decreased food pellet intake. FRU fed animals displayed increased plasma glucose, and cholesterol levels, which was not observed in overnight-fasted animals. Superoxide dismutase (SOD), and catalase (CAT) activities were markedly decreased in the prefrontal cortex of animals receiving FRU diet, while glutathione peroxidase (GPx) slightly increased. Liver (lower GPx), striatum (higher SOD and lower CAT), and hippocampus (no changes) were less impacted. No changes were observed in glutathione reductase, and thioredoxin reductase activities, two ancillary enzymes for peroxide detoxification. FRU intake did not alter serotonin, dopamine, and norepinephrine levels in the hippocampus, prefrontal cortex, and striatum. No significant alterations were observed in working, and short-term spatial memory; and in anxiety- and depressive-like behaviors in animals treated with FRU. Increased locomotor activity was observed in FRU-fed middle-aged mice, as evaluated in the open field, elevated plus-maze, Y maze, and object location tasks. Overall, these results demonstrate that high FRU consumption can disturb antioxidant defenses, and increase locomotor activity in middle-aged mice, open the opportunity for further studies to address the underlying mechanisms related to these findings.

Assuntos

Catalase/metabolismo , Frutose/farmacologia , Locomoção/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Teste de Labirinto em Cruz Elevado , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Teste de Campo Aberto/efeitos dos fármacos

RESUMO

Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

Assuntos

Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Monoaminoxidase/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Tiramina/análogos & derivados , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bupropiona/farmacologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Fluoxetina/farmacologia , Imipramina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Norepinefrina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tiramina/farmacologia

RESUMO

BACKGROUND: Chronic exposure to stress may dysregulate the hypothalamic-pituitary-adrenal axis and brain monoamine levels, contributing to the development of ethanol dependence. Exposure to chronic social defeat stress may impact ethanol-related effects, neural, and endocrine functions. AIM: This study assessed ethanol-induced locomotor activity, corticosterone responses, and brain monoamine levels in Swiss albino mice 10 days post-exposure to chronic social defeat stress. METHODS: During a period of 10 days, male Swiss mice were exposed to daily defeat episodes, followed by housing with an aggressive mouse for 24 h. Control mice were housed in pairs and rotated every 24 h. Ten days post-stress, locomotor behavior was recorded after a challenge with ethanol (2.2 g/kg; intraperitoneal) or saline. After the test, blood and brain samples were collected for determination of plasma corticosterone and brain monoamines across different brain areas through high-performance liquid chromatography. RESULTS: Defeated mice failed to show a stimulant locomotor response to ethanol, while controls displayed the expected ethanol-induced stimulation. Ethanol increased plasma corticosterone levels, with lower corticosterone secretion in defeated mice. Brain monoamines were affected by social defeat and ethanol, varying in different brain regions. Social stress reduced levels of dopamine, noradrenaline, and serotonin in the hypothalamus. Defeated mice presented reduced serotonin and dopamine levels in the frontal cortex. In the striatum, ethanol treatment increased dopamine levels in controls, but failed to do so in defeated mice. CONCLUSIONS: Our results suggest that chronic exposure to social defeat blunted ethanol-induced locomotor stimulation, and reduced ethanol-induced corticosterone secretion. Social stress promoted differential reductions in brain monoamine levels in the hypothalamus and frontal cortex and blunted ethanol-induced dopamine increases in the striatum.

Assuntos

Monoaminas Biogênicas/metabolismo , Corticosterona/metabolismo , Etanol/farmacologia , Estresse Psicológico/psicologia , Agressão , Animais , Química Encefálica/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Estimulação Química , Estresse Psicológico/metabolismo

RESUMO

Fibromyalgia is characterised mainly by symptoms of chronic widespread pain and comorbidities like depression. Although these symptoms cause a notable impact on the patient's quality of life, the underlying aetiology and pathophysiology of this disease remain incompletely elucidated. The transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor that is involved in the development of nociceptive and depressive behaviours, while α-spinasterol, a multitarget TRPV1 antagonist and cyclooxygenase inhibitor, presents antinociceptive and antidepressant effects. The present study investigated the involvement of the TRPV1 channel and the possible effects of α-spinasterol on nociceptive and depressive-like behaviours in an experimental fibromyalgia model. The fibromyalgia model was induced with a subcutaneous (s.c.) injection of reserpine (1 mg/kg) once daily for 3 consecutive days in male Swiss mice. Reserpine administration depleted monoamines and caused mechanical allodynia. This dysfunction was inhibited by SB-366791 (1 mg/kg, oral route [p.o.]), a selective TRPV1 antagonist, with a maximum inhibition (Imax) of 73.4 ± 15.5%, or by the single or 3-day-repeated administration of α-spinasterol (0.3 mg/kg, p.o.), with an Imax of 72.8 ± 17.8% and 78.9 ± 32.9%, respectively. SB-366791 also inhibited the increase of the reserpine-induced immobility time, with an Imax of 100%, while α-spinasterol inhibited this parameter with an Imax of 98.2 ± 21.5% and 100%, by single or repeated administration, respectively. The reserpine-induced mechanical allodynia and the thermal hyperalgesia were abolished by TRPV1-positive fibers desensitization induced by previous resiniferatoxin (RTX) administration. In summary, the TRPV1 channel is involved in the development and maintenance of nociception and depressive-like behaviours in a fibromyalgia model, while the α-spinasterol has therapeutic potential to treat the pain and depression symptoms in fibromyalgia patients.

Assuntos

Fibromialgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Estigmasterol/análogos & derivados , Canais de Cátion TRPV/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Qualidade de Vida , Estigmasterol/farmacologia , Canais de Cátion TRPV/metabolismo

RESUMO

Abstract Introduction Systemic administration of pentylenetetrazole (PTZ) causes brain damage (BD), and triggers a series of morphological and neurochemical changes, which in turn bring about behavioral, cognitive, and motor deficits. Serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels are controlled by various brain structures and these levels are related to motor activity; however, the concentration of these neurotransmitters during the postictal process remains unknown. Objective We investigated the concentration of 5-HT, NA and DA in the hippocampus, cerebellum, and cortex on motor deficit during the postictal stage. Method Eighteen male Wistar rats (300 g) assigned to two groups: control (n = 9, saline solution) and experimental (n = 9, PTZ) were used. Myoclonic shakes were counted and motor behavior assessments were recorded during three hours post PTZ injection (90 mg/kg). The cortex, cerebellum, and hippocampus of each rat were dissected to determine the 5-HT, DA, and NA concentration by high performance liquid chromatography. Results PTZ induced a significant increase in total 5-HT and DA levels in the hippocampus and cortex; in the cerebellum there was a significant increase in the concentration of 5-HT and NA. The presence of myoclonic shakes as well as a marked motor deficit in the experimental group were significantly different in comparison to the control. Discussion and conclusion 5-HT modifies the concentration of other monoamines directly involved in motor aspects such as NA and DA in the hippocampus, cerebellum, and cortex during the postictal process.

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Resumen Introducción La administración sistémica de pentilentetrazol (PTZ) causa daño cerebral y desencadena una serie de cambios morfológicos y neuroquímicos que a su vez provocan déficits conductuales, cognitivos y motores. Los niveles de serotonina (5-HT), dopamina (DA) y noradrenalina (NA) son modulados por varias estructuras cerebrales y sus concentraciones se relacionan con la actividad motora; sin embargo, se desconoce la concentración de estos neurotransmisores durante el proceso postictal. Objetivo Evaluar la manera en que la concentración de 5-HT, NA y DA en el hipocampo, el cerebelo y la corteza influye en el déficit motor durante la etapa postictal. Método Se utilizaron 18 ratas macho Wistar (300 g), divididas en dos grupos: control (n = 9, solución salina) y experimental (n = 9, PTZ). Se registraron las sacudidas mioclónicas y se evaluó el comportamiento motor durante tres horas después de la inyección de PTZ (90 mg/kg). Se extrajeron la corteza, el cerebelo y el hipocampo de cada rata para determinar la concentración de 5-HT, DA y NA mediante cromatografía líquida de alta resolución. Resultados La administración de PTZ indujo un aumento significativo en los niveles totales de 5-HT y DA en el hipocampo y la corteza; en el cerebelo hubo un aumento significativo en la concentración de 5-HT y NA. Se encontró una diferencia significativa entre el grupo experimental y control con respecto a las sacudidas mioclónicas; asimismo, los animales del grupo experimental mostraron un marcado déficit motor. Discusión y conclusión La 5-HT modula la concentración de otras monoaminas involucradas directamente en aspectos motores tal como NA y DA en el hipocampo, el cerebelo y la corteza durante el proceso postictal.