RESUMO
Between the neurotransmission systems modulated by alcohol, the opioid system has been receiving attention in studies that seek to understand its relationship to the effects of addictive substances and different neuropsychiatric disorders. The use of naltrexone stands out in determining the mechanisms of the opioid system, as it acts as an opioid antagonist and consequently generates neurochemical responses. This study aimed to evaluate the pharmacological modulation of opioids on behavioral and neurobiological aspects in adult zebrafish submitted to the protocol of repeated exposure to ethanol and treated with naltrexone. Opioid modulation using naltrexone has been shown to modulate anxiety-like behavior, presenting anxiolytic properties in isolation, in addition to reversing the anxiogenic effect of ethanol through the Novel tank and Light/dark test. Naltrexone increased serotonin and dopamine levels, while ethanol antagonized these effects. In contrast, the interaction between ethanol and naltrexone raised noradrenaline levels. Naltrexone altered glutamate levels, however, ethanol reversed it. Ethanol acted on glutamate transporters increasing their activities, while naltrexone treatment reduced activities. No significant results were found in the pro-oxidant parameters, however, ethanol reduced SOD activity while naltrexone reversed. The same occurred in CAT activity. Also, naltrexone up-regulated the expression of genes related to the dopaminergic, glutamatergic, and opioid systems. The genes used as markers of the inflammatory process and glial activity were modulated by ethanol and together with naltrexone, respectively. Taken together, our findings reinforce the importance of opioid signaling on biochemical and molecular bases related to neuropsychiatric behaviors and diseases, such as anxiety and substance dependence.
Assuntos
Comportamento Animal , Etanol , Naltrexona , Antagonistas de Entorpecentes , Peixe-Zebra , Animais , Naltrexona/farmacologia , Etanol/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Masculino , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Dopamina/metabolismo , Serotonina/metabolismoRESUMO
Consumption of alcoholic beverages during pregnancy is directly related to the establishment of fetal alcohol spectrum disorders (FASD), which includes craniofacial changes, body growth restriction, and neurodevelopment impairments. Proper functioning of the central nervous system (CNS) depends on blood-brain barrier (BBB) development, which is formed by interactions of vascular endothelial cells, pericytes, astrocytes, and basal lamina. Gestational exposure to ethanol has been demonstrated to impair CNS development; however, little is known about ethanol modulation of blood circulating factors and impacts on human developing BBB. Here we investigated the prevalence of alcohol consumption during pregnancy and found that 27% of pregnant women reported alcohol consumption, mainly in the first trimester. Control and alcohol-exposed newborns showed no differences in weight, length, and appearance, pulse, grimace, activity, respiration (APGAR) score at birth. In vitro, we cultivated human brain microcapillary endothelial cells (HBMEC) and treated with umbilical cord blood serum (UCBS) from control (S-Control) newborns or ethanol-exposed ones (S-Ethanol). S-Ethanol treatment induced 68% and 38% decreases in protein levels of ZO-1 (tight junction) and GLUT-1 (glucose transporter type-1), respectively, increased endothelial monolayer permeability, migratory potential impairment, and changes in angiogenesis-related secreted proteins profile, compared to S-Control treatments. UCBS proteomics revealed a total of 392 proteins, 10 exclusively found in S-Ethanol, mostly related to innate and adaptive immunity and tissue injury response. These results suggest that gestational exposure to ethanol contributes to blood altered protein profiles triggering BBB endothelial.
Assuntos
Consumo de Bebidas Alcoólicas , Barreira Hematoencefálica , Células Endoteliais , Etanol , Sangue Fetal , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Recém-Nascido , Consumo de Bebidas Alcoólicas/efeitos adversos , Etanol/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Adulto , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Células Cultivadas , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Masculino , Microvasos/patologia , Microvasos/metabolismo , Microvasos/efeitos dos fármacosRESUMO
Alcohol consumption is a worldwide concern that causes 5 % of the global disease burden and contributes to 3 million deaths per year. Several studies suggest an increase in alcohol drinking and alcohol related problems. Alcohol Use Disorder (formerly referred as alcoholism or alcohol addiction) is one of many possible outcomes of an early and prolonged alcohol consumption and it is highly comorbid with anxiety disorders, impulsivity and memory deficits among others. In this review we approach recent data about global and American prevalence of alcohol use and discuss different factors that contribute to alcohol consumption. Furthermore, we revise evidence of ethanol effects on anxiety-like behaviors, impulsivity and spatial memory. Lastly, we look at the Omega-3 fatty acid as a possible course of action in mitigating the aforementioned deleterious effects of alcohol consumption.
Assuntos
Ansiedade , Ácidos Graxos Ômega-3 , Comportamento Impulsivo , Memória Espacial , Humanos , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Animais , Ansiedade/tratamento farmacológico , Etanol/farmacologia , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologiaRESUMO
Pharmacotherapy in Alcohol Withdrawal Syndrome (AWS), which is a mental disorder, generally involves benzodiazepines due to their action via GABA, but their side effects, such as excessive sedation, mental confusion and risk of dependence, are considerable. It is important to investigate the anxiolytic potential of plants such as Caryocar coriaceum, due to the presence of secondary metabolic compounds, such as isoquercitrin, capable of promoting the reduction of anxiety during AWS. We evaluated the anxiolytic-like potential of ethanolic extracts from the leaves (EEPL) and pulp (EEPP) of C. coriaceum, and its major compound, isoquercitrin (IsoQuer), in adult zebrafish (Danio rerio) during alcohol withdrawal. Adult zebrafish (nâ¯=â¯8 per group) were treated (20 µL; p.o) with EEPL, or EEPP or IsoQuer (0.01 or 0.05 or 0.1 or 0.5 or 1.0â¯mg/mL) and submitted to the 96-hour acute toxicity test. Flumazenil in adult zebrafish and molecular Docking of IsoQuer were used to investigate the GABAergic involvement. Finally, the anxiolytic-like activity was evaluated during alcohol withdrawal in adult zebrafish. The results indicated that EEPL, EEPP and IsoQuer are safe and have no sedative effect on adult zebrafish. Furthermore, they demonstrated a pharmacological potential in the treatment of alcohol withdrawal-induced anxiety, mediated by the GABAergic system, evidenced in the in-silico study by the stable isoquercitrin-GABAA complex, the main constituent of the extracts. These findings suggest an anxiolytic herbal potential of C. coriaceum and isoquercitrin, providing an alternative for the treatment of anxiety associated with AWS.
Assuntos
Ansiolíticos , Ansiedade , Etanol , Extratos Vegetais , Quercetina , Síndrome de Abstinência a Substâncias , Peixe-Zebra , Animais , Quercetina/farmacologia , Quercetina/análogos & derivados , Extratos Vegetais/farmacologia , Ansiedade/tratamento farmacológico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Ansiolíticos/farmacologia , Etanol/farmacologia , Masculino , Modelos Animais de Doenças , Folhas de Planta/química , Flumazenil/farmacologia , Comportamento Animal/efeitos dos fármacosRESUMO
Alcohol is widely consumed worldwide and its abuse can cause cognitive dysfunction, affecting memory and learning due to several neurophysiological changes. An imbalance in several neurotransmitters, including the cholinergic and glutamatergic systems, have been implicated in these effects. Zebrafish are sensitive to alcohol, respond to reward stimuli, and tolerate and exhibit withdrawal behaviors. Therefore, we investigated the effects of repetitive exposure to ethanol (REE) and the NMDA receptor antagonist dizocilpine (MK-801) on memory acquisition and glutamatergic and cholinergic neurotransmission. Memory was assessed using the inhibitory avoidance and object recognition tasks. Brain glutamate levels and the activity of Na+-dependent transporters were evaluated as indexes of glutamatergic activity, while acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), enzyme activity were evaluated as indexes of cholinergic activity. Behavioral assessments showed that REE impaired aversive and spatial memory, an effect that MK-801 mimicked. Glutamate levels, but not transporter activity, were significantly lower in the REE group; similarly, REE increased the activity of AChE, but not ChAT, activity. These findings suggest that intermittent exposure to ethanol leads to impairments in zebrafish memory consolidation, and that these effects could be associated with alterations in parameters related to neurotransmission systems mediated by glutamate and acetylcholine. These results provide a better understanding of the neurophysiological and behavioral changes caused by repetitive alcohol use.
Assuntos
Encéfalo , Maleato de Dizocilpina , Etanol , Ácido Glutâmico , Memória , Transmissão Sináptica , Peixe-Zebra , Animais , Etanol/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Maleato de Dizocilpina/farmacologia , Ácido Glutâmico/metabolismo , Memória/efeitos dos fármacos , Masculino , Acetilcolinesterase/metabolismo , Aprendizagem da Esquiva/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismoRESUMO
Ethanol stress in Saccharomyces cerevisiae is a well-studied phenomenon, but pinpointing specific genes or polymorphisms governing ethanol tolerance remains a subject of ongoing debate. Naturally found in sugar-rich environments, this yeast has evolved to withstand high ethanol concentrations, primarily produced during fermentation in the presence of suitable oxygen or sugar levels. Originally a defense mechanism against competing microorganisms, yeast-produced ethanol is now a cornerstone of brewing and bioethanol industries, where customized yeasts require high ethanol resistance for economic viability. However, yeast strains exhibit varying degrees of ethanol tolerance, ranging from 8 to 20%, making the genetic architecture of this trait complex and challenging to decipher. In this study, we introduce a novel QTL mapping pipeline to investigate the genetic markers underlying ethanol tolerance in an industrial bioethanol S. cerevisiae strain. By calculating missense mutation frequency in an allele located in a prominent QTL region within a population of 1011 S. cerevisiae strains, we uncovered rare occurrences in gene IRA2. Following molecular validation, we confirmed the significant contribution of this gene to ethanol tolerance, particularly in concentrations exceeding 12% of ethanol. IRA2 pivotal role in stress tolerance due to its participation in the Ras-cAMP pathway was further supported by its involvement in other tolerance responses, including thermotolerance, low pH tolerance, and resistance to acetic acid. Understanding the genetic basis of ethanol stress in S. cerevisiae holds promise for developing robust yeast strains tailored for industrial applications.
Assuntos
Mapeamento Cromossômico , Etanol , Locos de Características Quantitativas , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Etanol/metabolismo , Etanol/farmacologia , Proteínas de Saccharomyces cerevisiae/genética , Fermentação/genética , Mutação de Sentido Incorreto , Proteínas Ativadoras de GTPaseRESUMO
RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.
Assuntos
Alcaloides , Azocinas , Baclofeno , Condicionamento Operante , Etanol , Agonistas dos Receptores de GABA-B , Agonistas Nicotínicos , Núcleo Accumbens , Quinolizinas , Ratos Wistar , Autoadministração , Animais , Masculino , Baclofeno/farmacologia , Baclofeno/administração & dosagem , Ratos , Alcaloides/farmacologia , Alcaloides/administração & dosagem , Azocinas/farmacologia , Azocinas/administração & dosagem , Quinolizinas/farmacologia , Quinolizinas/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Agonistas dos Receptores de GABA-B/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Etanol/administração & dosagem , Etanol/farmacologia , Condicionamento Operante/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/administração & dosagem , Administração Oral , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Alcaloides QuinolizidínicosRESUMO
Although the industrial production of butanol has been carried out for decades by bacteria of the Clostridium species, recent studies have shown the use of the yeast Saccharomyces cerevisiae as a promising alternative. While the production of n-butanol by this yeast is still very far from its tolerability (up to 2% butanol), the improvement in the tolerance can lead to an increase in butanol production. The aim of the present work was to evaluate the adaptive capacity of the laboratory strain X2180-1B and the Brazilian ethanol-producing strain CAT-1 when submitted to two strategies of adaptive laboratory Evolution (ALE) in butanol. The strains were submitted, in parallel, to ALE with successive passages or with UV irradiation, using 1% butanol as selection pressure. Despite initially showing greater tolerance to butanol, the CAT-1 strain did not show great improvements after being submitted to ALE. Already the laboratory strain X2180-1B showed an incredible increase in butanol tolerance, starting from a condition of inability to grow in 1% butanol, to the capacity to grow in this same condition. With emphasis on the X2180_n100#28 isolated colony that presented the highest maximum specific growth rate among all isolated colonies, we believe that this colony has good potential to be used as a model yeast for understanding the mechanisms that involve tolerance to alcohols and other inhibitory compounds.
Assuntos
Butanóis , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Butanóis/metabolismo , Fermentação , Etanol/metabolismo , Etanol/farmacologia , 1-Butanol/metabolismo , Raios Ultravioleta , Adaptação FisiológicaRESUMO
Exposure to alcohol during adolescence impacts cortical and limbic brain regions undergoing maturation. In rodent models, long-term effects on behavior and neurophysiology have been described after adolescent intermittent ethanol (AIE), especially in males. We hypothesized that AIE in female rats increases conditional approach to a reward-predictive cue and corresponding neuronal activity in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc). We evaluated behavior and neuronal firing after AIE (5 g/kg intragastric) or water (CON) in adult female rats. Both AIE and CON groups expressed a ST phenotype, and AIE marginally increased sign-tracking (ST) and decreased goal-tracking (GT) metrics. NAc neurons exhibited phasic firing patterns to the conditional stimulus (CS), with no differences between groups. In contrast, neuronal firing in the OFC of AIE animals was greater at CS onset and offset than in CON animals. During reward omission, OFC responses to CS offset normalized to CON levels, but enhanced OFC firing to CS onset persisted in AIE. We suggest that the enhanced OFC neural activity observed in AIE rats to the CS could contribute to behavioral inflexibility. Ultimately, AIE persistently impacts the neurocircuitry of reward-motivated behavior in female rats.
Assuntos
Etanol , Núcleo Accumbens , Córtex Pré-Frontal , Recompensa , Animais , Feminino , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Etanol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Ratos Sprague-DawleyRESUMO
Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.
Assuntos
Comportamento de Procura de Droga , Etanol , Extinção Psicológica , Núcleo Accumbens , Ratos Long-Evans , Animais , Núcleo Accumbens/efeitos dos fármacos , Masculino , Etanol/administração & dosagem , Etanol/farmacologia , Comportamento de Procura de Droga/fisiologia , Ratos , Extinção Psicológica/fisiologia , Extinção Psicológica/efeitos dos fármacos , Autoadministração , Vias Neurais/fisiologia , Alcoolismo , Sinais (Psicologia) , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Baclofeno/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Muscimol/farmacologiaRESUMO
Fungal infections in neonatal intensive care units (NICU) are mainly related to Candida species, with high mortality rates. They are predominantly of endogenous origin, however, cross-infection transmitted by healthcare professionals' hands has occurred. The aim of this study was to identify Candida species isolated from the hands of healthcare professionals in a NICU before and after hygiene with 70% ethanol-based gel and evaluate virulence factors DNase, phospholipase, proteinase, hemolysin, biofilm biomass production, and metabolic activity. In vitro antifungal susceptibility testing and similarity by random amplified polymorphic DNA (RAPD) were also performed. C. parapsilosis complex was the most frequent species (57.1%); all isolates presented at least one virulence factor; three isolates (Candida parapsilosis complex) were resistant to amphotericin B, two (Candida famata [currently Debaryomyces hansenii] and Candida guilliermondii [currently Meyerozyma guilliermondii]) was resistant to micafungin, and six (Candida parapsilosis complex, Candida guilliermondii [=Meyerozyma guilliermondii], Candida viswanathi, Candida catenulata [currently Diutina catenulata] and Candida lusitaniae [currently Clavispora lusitaniae]) were resistant to fluconazole. Molecular analysis by RAPD revealed two clusters of identical strains that were in the hands of distinct professionals. Candida spp. were isolated even after hygiene with 70% ethanol-based gel, highlighting the importance of stricter basic measures for hospital infection control to prevent nosocomial transmission.
Assuntos
Antifúngicos , Candida , Infecção Hospitalar , Etanol , Mãos , Testes de Sensibilidade Microbiana , Fatores de Virulência , Humanos , Mãos/microbiologia , Antifúngicos/farmacologia , Fatores de Virulência/genética , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candida/genética , Candida/patogenicidade , Etanol/farmacologia , Infecção Hospitalar/microbiologia , Infecção Hospitalar/prevenção & controle , Candidíase/microbiologia , Pessoal de Saúde , Técnica de Amplificação ao Acaso de DNA Polimórfico , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Unidades de Terapia Intensiva Neonatal , Farmacorresistência Fúngica , Géis , Desinfecção das MãosRESUMO
Long noncoding RNAs (lncRNAs) are regulatory RNAs. Saccharomyces cerevisiae strains transcribe hundreds of lncRNAs. LncRNAs can regulate the expression of adjacent genes (cis-regulation) or distant genes from lncRNAs (trans-regulation). Here, we analyzed the potential global cis and trans-regulation of lncRNAs of yeast subjected to ethanol stress. For potential cis regulation, for BMA641-A and S288C strains, we observed that most lncRNA-neighbor gene pairs increased the expression at a certain point followed by a decrease, and vice versa. Based on the transcriptome profile and triple helix prediction between lncRNAs and promoters of coding genes, we observed nine different ways of potential trans regulation that work in a strain-specific manner. Our data provide an initial landscape of potential cis and trans regulation in yeast, which seems to be strain-specific.
Assuntos
Etanol , Regulação Fúngica da Expressão Gênica , RNA Longo não Codificante , Saccharomyces cerevisiae , Estresse Fisiológico , Saccharomyces cerevisiae/genética , RNA Longo não Codificante/genética , Etanol/farmacologia , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Estresse Fisiológico/genética , Regiões Promotoras Genéticas , RNA Fúngico/genética , RNA Fúngico/metabolismo , Perfilação da Expressão Gênica/métodos , TranscriptomaRESUMO
AIMS: Glycine receptors (GlyRs) are potentiated by physiologically relevant concentrations of ethanol, and mutations in the intracellular loop of α1 and α2 subunits reduced the effect of the drug. Knock-in (KI) mice having these individual mutations revealed that α1 and α2 subunits played a role in ethanol-induced sedation and ethanol intake. In this study, we wanted to examine if the effects of stacking both mutations in a 2xKI mouse model (α1/α2) generated by a selective breeding strategy further impacted cellular and behavioral responses to ethanol. MAIN METHODS: We used electrophysiological recordings to examine ethanol's effect on GlyRs and evaluated ethanol-induced neuronal activation using c-Fos immunoreactivity and the genetically encoded calcium indicator GCaMP6s in the nucleus accumbens (nAc). We also examined ethanol-induced behavior using open field, loss of the righting response, and drinking in the dark (DID) paradigm. KEY FINDINGS: Ethanol did not potentiate GlyRs nor affect neuronal excitability in the nAc from 2xKI. Moreover, ethanol decreased the Ca2+ signal in WT mice, whereas there were no changes in the signal in 2xKI mice. Interestingly, there was an increase in c-Fos baseline in the 2xKI mice in the absence of ethanol. Behavioral assays showed that 2xKI mice recovered faster from a sedative dose of ethanol and had higher ethanol intake on the first test day of the DID test than WT mice. Interestingly, an open-field assay showed that 2xKI mice displayed less anxiety-like behavior than WT mice. SIGNIFICANCE: The results indicate that α1 and α2 subunits are biologically relevant targets for regulating sedative effects and ethanol consumption.
Assuntos
Etanol , Técnicas de Introdução de Genes , Receptores de Glicina , Animais , Etanol/farmacologia , Receptores de Glicina/genética , Receptores de Glicina/metabolismo , Camundongos , Masculino , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos Transgênicos , Receptores de GABA-ARESUMO
Alcohol, a widely commercialized psychotropic drug, and the benzodiazepine Flunitrazepam, an anxiolytic widely prescribed for patients with anxiety and insomnia problems, are well known drugs and both act on the central nervous system. The misuse and the association of these two drugs are public health concerns in several countries and could cause momentary, long-lasting and even lethal neurophysiological problems due to the potentiation of their adverse effects in synergy. The present study observed the result of the association of these drugs on electrophysiological responses in the brain, heart, and respiratory rate in Wistar rats. 8 experimental groups were determined: control, one alcohol group (20% at a dose of 1 ml/100 g VO), three Flunitrazepam groups (doses 0.1; 0.2 and 0.3 mg/kg) and three alcohol-Flunitrazepam groups (20% at a dose of 1 ml/100 g VO of alcohol, combined with 0.1; 0.2 and 0.3 mg/kg of Flunitrazepam, respectively). The results showed that there was a more pronounced reduction in alpha and theta wave power in the alcohol-Flunitrazepam groups, a decrease in the power of beta oscillations and greater sedation. There was a progressive decrease in respiratory rate linked to the increase of Flunitrazepam dose in the alcohol-Flunitrazepam associated administration. It was observed alteration in heart rate and Q-T interval in high doses of Flunitrazepam. Therefore, we conclude that the association alcohol-Flunitrazepam presented deepening of depressant synergistic effects according to the increase in the dose of the benzodiazepine, and this could cause alterations in low frequency brain oscillations, breathing, and hemodynamics of the patient.
Assuntos
Sinergismo Farmacológico , Eletrocardiografia , Etanol , Flunitrazepam , Ratos Wistar , Animais , Masculino , Flunitrazepam/farmacologia , Eletrocardiografia/efeitos dos fármacos , Etanol/farmacologia , Eletrocorticografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/administração & dosagem , Ratos , Taxa Respiratória/efeitos dos fármacos , Ansiolíticos/farmacologia , Relação Dose-Resposta a Droga , Encéfalo/efeitos dos fármacosRESUMO
Research has identified the large conductance voltage- and calcium-activated potassium channel (BK) as a key regulator of neuronal excitability genetically associated to behavioral alcohol tolerance. Sensitivity to ethanol at the molecular level is characterized by acute potentiation of channel activity. BK isoforms show variations in alcohol sensitivity and are differentially distributed on the plasma membrane surface in response to prolonged exposure. MicroRNA (MiRNA) targeting of alcohol-sensitive isoforms coupled with active internalization of BK channels in response to ethanol are believed to be key in establishing homeostatic adaptations that produce persistent changes within the plasma membrane of neurons. In fact, microRNA 9 (miR-9) upregulated expression is a key event in persistent alcohol tolerance mediating acute EtOH desensitization of BK channels. The exact nature of these interactions remains a current topic of discussion. To further study the effects of miR-9 on the expression and distribution of BK channel isoforms we designed an experimental model by transfecting human BK channel isoforms ZERO heterologous constructs in human embryonic kidney cells 293 (HEK293) cells respectively expressing 2.1 (miR-9 responsive), 2.2 (unresponsive) and control (no sequence) 3'untranslated region (3'UTR) miRNA recognition sites. We used imaging techniques to characterize the stably transfected monoclonal cell lines, and electrophysiology to validate channel activity. Finally, we used immunocytochemistry to validate isoform responsiveness to miR-9. Our findings suggest the cell lines were successfully transfected to express either the 2.1 or 2.2 version of ZERO. Patch clamp recordings confirm that these channels retain their functionality and immunohistochemistry shows differential responses to miR-9, making these cells viable for use in future alcohol dependence studies.
Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta , MicroRNAs , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Regiões 3' não Traduzidas/genética , Células HEK293 , Etanol/farmacologia , MicroRNAs/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Rim/metabolismo , Cálcio/metabolismoRESUMO
INTRODUCTION: Alcohol ingestion influences metabolism during a subsequent exercise session, as evidenced by increased blood lactate concentration during fixed-intensity exercise. Therefore, augmented blood concentrations of alcohol may interfere with the anaerobic metabolism during high-intensity, short-duration exercise bout, thereby leading to impaired athletic performance. OBJECTIVE: This study investigated whether the acute ingestion of alcohol as ethanol modulates performance parameters derived from the power-duration relationship in a 3-min all-out cycling test that allows for identifying the power output related to heavy and severe exercise intensities. METHODS: Twenty-four recreationally active cyclists (16 men and 8 women) ingested a beverage containing either 0.4 g ethanol.kg-1 body mass (EtOH) or a placebo (PLA) solution. Thirty minutes following ingestion, they completed a 3-min all-out test to measure power output and determine the end-test power (EP) and the work done above EP (WEP). RESULTS: Alcohol ingestion decreased WEP by 16% (EtOH: 5.6 ± 2.5 kJ vs. PLA: 6.7 ± 2.4 kJ; P = .003) but did not change EP (EtOH: 211 ± 44 W vs. PLA: 212 ± 44 W; P = .671). The alcohol-mediated effect in WEP was not influenced when controlling for participants' sex or accuracy in identifying the beverage ingested. CONCLUSION: Our data indicate that alcohol ingestion impaired the anaerobic work capacity, as evidenced by the reduction in WEP during the 3-min all-out test. Moreover, the ability to exercise at an intensity above the heavy domain may be decreased after ingestion of a moderate alcohol dose.
Assuntos
Teste de Esforço , Exercício Físico , Masculino , Humanos , Feminino , Etanol/farmacologia , Ingestão de Alimentos , PoliésteresRESUMO
The tick Rhipicephalus microplus is a parasite of great importance in cattle breeding. It is responsible for huge economic losses. The application of synthetic acaricides is used as a form of control. However, resistant strains have been selected over the years, making it necessary to search for new alternative formulations. The present study aimed to formulate biodegradable films impregnated with the terpenes carvacrol and thymol and evaluate their efficacy on larvae and adults of R. microplus through in vitro tests. The following formulations were prepared: Film 1 (starch based); Film 2 (based on starch and glycerol); Film 1 + Carvarcol or Thymol; Film 2 + Carvarcol or Thymol. Terpenes had a final concentration of 5.0â¯mg/mL. To evaluate the formulations on larvae, the immersion test was performed by dividing into six groups according to the concentration of terpenes: 5.0, 2.5, 1.25, 0.625, 0.313, 0.156â¯mg/mL and the control groups: 1% ethanol solution; 10% ethanol solution; Film 1; and Film 2. For the evaluations on adult ticks, ten experimental groups (n = 10) were used: 1) Carvacrol; 2) Film 1 + Carvacrol; 3) Film 2 + Carvacrol; 4) Thymol; 5) Film 1 + Thymol; 6) Film 2 + Thymol; 7) Distilled water; 8) 10% ethanol solution; 9) Film 1; and 10) Film 2. In experimental groups 1-6, carvacrol and thymol (free or incorporated in two different biodegradable film formulations) were evaluated at the same concentration (5.0â¯mg/mL). Each group of ticks was immersed in their respective solutions for five minutes. The results of the tests on larvae showed that the Film 1 + thymol and Film 2 + carvacrol formulations had the lowest lethal concentrations (0.076 and 0.255â¯mg/mL, respectively), values up to 9.0-fold lower than the monoterpenes tested outside the formulation. Carvacrol and thymol at the concentrations tested were effective in controlling engorged females with a percentage of 32.2% and 63.8%, respectively. When incorporated into biodegradable film formulations, these monoterpenes showed much greater efficacy. Film 1 + carvacrol and Film 2 + carvacrol with control percentages of 71.6% and 97.2%, respectively, while the formulations Film 1 + thymol and Film 2 + thymol showed values of 96.9% and 100.0%. The tick control activity of the biopolymer formulations with thymol and carvacrol was demonstrated through the high mortality rates of larvae and engorged females of the tick R. microplus. Therefore, the results obtained indicate that these formulations have great potential for tick control mainly because of the percentage of control up to 100% in engorged females in in vitro tests.
Assuntos
Acaricidas , Cimenos , Rhipicephalus , Feminino , Animais , Bovinos , Timol/farmacologia , Terpenos/farmacologia , Zea mays , Amido/farmacologia , Melhoramento Vegetal , Monoterpenos/farmacologia , Acaricidas/farmacologia , Etanol/farmacologia , LarvaRESUMO
RATIONALE: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. OBJECTIVES: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. RESULTS: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. CONCLUSIONS: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption.
Assuntos
Consumo de Bebidas Alcoólicas , Córtex Pré-Frontal , Derrota Social , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Camundongos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Etanol/administração & dosagem , Etanol/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Doença CrônicaRESUMO
Taurine is a non-essential ß sulfonated amino acid involved in a plethora of biological functions in the mammalian central nervous system. Taurine is easily accessible in energy drinks for human consumption. Previous preclinical and clinical reports suggest that acute systemic administration of taurine could inhibit some of the behavioral and metabolic effects of alcohol use disorder. Overall, both in rodent and human studies, acute taurine administration reduced voluntary alcohol intake. This study aimed to assess the pharmacological effects of taurine (intracerebroventricular; i.c.v.) on ethanol intake/preference of rats either control (i.e., alcohol naïve) or forced ethanol intake (since juvenile age with a chronic intermittent access model). In addition, to explore anxiety-like behavior (through defensive burying behavior test) as pharmacological control of taurine. We found that acute (i.c.v.) taurine reduced alcohol consumption, i.e., taurine significantly decreased both alcohol intake and preference in adult male Wistar rats. Moreover, taurine elicits an anxiolytic-like effect in all administered groups independently of previous alcohol exposure.
Assuntos
Alcoolismo , Taurina , Humanos , Ratos , Animais , Masculino , Taurina/farmacologia , Ratos Wistar , Etanol/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , MamíferosRESUMO
To evaluate the effect of high-graduation chronic ethanol (EtOH) intake on bone and periodontal tissues of rats. Male Wistar rats (250 g) were divided into two groups of n = 12 each one. EtOH (5 ml of 3 g/kg) was administered to the experimental group by gastric gavage twice a day for 20 days and the control group received water under the same conditions. The rats were euthanized and used to perform biochemical determination in plasma and gingival tissue, and histological and biomechanical studies in the femur and mandibular tissues. Alcohol increased both TNFα (p < 0.01) and PGE2 (p < 0.05) in plasma and gingiva (p < 0.05) as compared to controls. In addition, EtOH increased the alveolar bone loss as evidenced by the increased distance between the cement enamel junction and the alveolar crest (p < 0.01), the lower % of interradicular bone expressed as bone area/total area (B.Ar/T.Ar, p < 0.05) and the larger periodontal space (p < 0.05), as compared to controls. Likewise, the mandibular microtomographic analysis in alcoholized rats revealed a lower % of interradicular bone volume/total volume (BV/TV, p < 0.05), greater trabecular separation (p < 0.05) and greater % trabecular porosity (p < 0.05) than controls. No biomechanical alteration was observed in lower jaws, while the femur of alcoholized rats presented a decrease in the structural bone properties (p < 0.001), as a systemic consequence of deterioration of the diaphyseal architecture (p < 0.01) without changes in material properties. The consumption of high doses of alcohol produces deleterious effects on periodontal tissues that could be due not only to local but also systemic effects.