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BACKGROUND: Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-D-aspartate (NMDA) and enhancement of inhibitory gamma-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABA(A) receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal. METHODS: Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal. RESULTS: Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal. CONCLUSIONS: These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism.
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Consumo de Bebidas Alcoólicas/prevenção & controle , Convulsões por Abstinência de Álcool/prevenção & controle , Etanol/administração & dosagem , Riluzol/uso terapêutico , Consumo de Bebidas Alcoólicas/fisiopatologia , Convulsões por Abstinência de Álcool/fisiopatologia , Animais , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esquema de Reforço , AutoadministraçãoRESUMO
Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by a hyperstimulated immune response, including elevated levels of inflammatory cytokines/chemokines and oligoclonal expansion of virus-specific CD8(+) T cells in the cerebrospinal fluid. Studies have shown that the HTLV-1 transactivator protein Tax is available for immune recognition by antigen presenting cells (APCs), such as dendritic cells (DCs). DCs are relevant to the pathogenesis of HAM/TSP because the presentation of Tax peptides by activated DCs to naïve CD8(+) T cells may play an important role in the induction of the Tax-specific immune response that is observed in HAM/TSP. In this study, a human cytokine protein array was used to study the secretion of cytokines by monocyte-derived DCs (MDDCs) exposed to Tax. Of the 16 cytokines analyzed, 6 cytokines were secreted in significantly high amounts (> or =2-fold), including Th1 cytokines (IFN-gamma, IL-12, and TNF-alpha) and C-C chemokines (Eotaxin, MCP-1, and MCP-3). Selected cytokines were further examined at two concentrations of Tax and at two time periods. Furthermore, a transient exposure to Tax did not result in any cytokine production when examined at three different time points after exposure, indicating that a prolonged presence of Tax is required for its activity. Finally, inhibition of the NF-kappaB signaling pathway by specific inhibitors, abrogated Tax-mediated cytokine secretion. Collectively, these findings suggest a role for Tax-induced cytokine secretion from MDDCs, which may be critical for the cellular activation and tissue damage that has been observed in HAM/TSP.
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Citocinas/biossíntese , Células Dendríticas/metabolismo , Produtos do Gene tax/fisiologia , Quimiocinas/biossíntese , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas In Vitro , NF-kappa B/metabolismo , Análise Serial de Proteínas , Transdução de SinaisRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0123861.].
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RATIONALE: Many of the biochemical, physiological, and behavioral effects of ethanol are known to be mediated by ionotropic glutamate receptors. Emerging evidence implicates metabotropic glutamate receptors (mGluRs) in the biobehavioral effects of ethanol and other drugs of abuse, but there is little information regarding the role of mGluRs in the reinforcing effects of ethanol. MATERIALS AND METHODS: Male C57BL/6J mice were trained to lever-press on a concurrent fixed ratio 1 schedule of ethanol (10% v/v) vs water reinforcement during 16-h sessions. Effects of mGluR1, mGluR2/3, and mGluR5 antagonists were then tested on parameters of ethanol self-administration behavior. RESULTS: The mGluR5 antagonist MPEP (1-10 mg/kg, i.p.) dose-dependently reduced ethanol-reinforced responding but had no effect on concurrent water-reinforced responding. Analysis of the temporal pattern of responding showed that MPEP reduced ethanol-reinforced responding during peak periods of behavior occurring during the early hours of the dark cycle. Further analysis showed that MPEP reduced the number of ethanol response bouts and bout-response rate. MPEP also produced a 13-fold delay in ethanol response onset (i.e., latency to the first response) with no corresponding effect on water response latency or locomotor activity. The mGluR1 antagonist CPCCOEt (1-10 mg/kg, i.p.) or the mGluR2/3 antagonist LY 341495 (1-30 mg/kg, i.p.) failed to alter ethanol- or water-reinforced responding. CONCLUSIONS: These data indicate that mGlu5 receptors selectively regulate the onset and maintenance of ethanol self-administration in a manner that is consistent with reduction in ethanol's reinforcement function.
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Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5 , Reforço Psicológico , AutoadministraçãoRESUMO
OBJECTIVE: The objective of this pilot study was to examine the effects of a brief, 6-week, 1.5-hour mind-body intervention for depression (MBID) in patients being treated for depression in 2 community health centers. DESIGN: The MBID taught techniques such as meditation that elicit the relaxation response (RR) in combination with additional resiliency-enhancing components. Clinical outcomes of 24 depressed patients were measured pre-MBID, at completion of MBID, and 3 months post-MBID, using the Center for Epidemiological Studies Depression Scale (CES-D 10), Quality of Life Scale (QoL5), SF-12 Health Survey (SF-12), and Health-Promoting Lifestyle Profile-II (HPLP-II). RESULTS: Significant post-treatment improvements were shown in depressive symptoms, spiritual growth, mental health, and quality of life, with a median CES-D 10 change from 17.5 (interquartile ratio [IQR] 13.3-22) to 12 (IQR 10-17.5; P<.001); a median HPLP-II Spiritual Growth subscale change from 2.0 (IQR 1.8-2.3) to 2.3 (IQR 2.0-3.0; P=.002) and a median HPLP-II Stress Management subscale change from 2.0 (IQR 1.8-2.4) to 2.4 (IQR 2.0-2.9; P=.027); significant improvement in median score on the QoL-5 from 53.3 (IQR 47.5-62.5) at baseline to 63.3 at endpoint (IQR 50-70; P=.008). Three-month follow-up data suggest that the improvement in outcomes were sustained 3 months after the intervention. CONCLUSIONS: Participation in a 6-week RR-based MBID is associated with an improvement in depression, spiritual growth, and mental health among depressed community health center patients.
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INTRODUCTION: Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) can profoundly affect quality of life and are influenced by stress and resiliency. The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined. METHODS: Nineteen IBS and 29 IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR-MBI), focusing on elicitation of the RR and cognitive skill building. Symptom questionnaires and inflammatory markers were assessed pre- and post-intervention, and at short-term follow-up. Peripheral blood transcriptome analysis was performed to identify genomic correlates of the RR-MBI. RESULTS: Pain Catastrophizing Scale scores improved significantly post-intervention for IBD and at short-term follow-up for IBS and IBD. Trait Anxiety scores, IBS Quality of Life, IBS Symptom Severity Index, and IBD Questionnaire scores improved significantly post-intervention and at short-term follow-up for IBS and IBD, respectively. RR-MBI altered expression of more genes in IBD (1059 genes) than in IBS (119 genes). In IBD, reduced expression of RR-MBI response genes was most significantly linked to inflammatory response, cell growth, proliferation, and oxidative stress-related pathways. In IBS, cell cycle regulation and DNA damage related gene sets were significantly upregulated after RR-MBI. Interactive network analysis of RR-affected pathways identified TNF, AKT and NF-κB as top focus molecules in IBS, while in IBD kinases (e.g. MAPK, P38 MAPK), inflammation (e.g. VEGF-C, NF-κB) and cell cycle and proliferation (e.g. UBC, APP) related genes emerged as top focus molecules. CONCLUSIONS: In this uncontrolled pilot study, participation in an RR-MBI was associated with improvements in disease-specific measures, trait anxiety, and pain catastrophizing in IBS and IBD patients. Moreover, observed gene expression changes suggest that NF-κB is a target focus molecule in both IBS and IBD-and that its regulation may contribute to counteracting the harmful effects of stress in both diseases. Larger, controlled studies are needed to confirm this preliminary finding. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02136745.
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Cognição , Regulação da Expressão Gênica , Doenças Inflamatórias Intestinais , Síndrome do Intestino Irritável , Terapias Mente-Corpo , Transcriptoma , Adolescente , Adulto , Idoso , Seguimentos , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/psicologia , Doenças Inflamatórias Intestinais/terapia , Síndrome do Intestino Irritável/sangue , Síndrome do Intestino Irritável/psicologia , Síndrome do Intestino Irritável/terapia , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
RATIONALE: A growing number of studies suggest that gamma-aminobutyric acid type-B (GABA(B)) receptor agonists reduce alcohol use and craving. OBJECTIVES: This study was designed to further clarify behavioral mechanism(s) by which GABA(B) agonists may decrease alcohol reinforcement. METHODS: Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA(B) agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA(B) agonists was examined in ethanol naive and self-administering mice. RESULTS: Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA(B) agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA(B) agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA(B) agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol. CONCLUSIONS: GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.
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Condicionamento Operante/efeitos dos fármacos , Etanol/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Hipnóticos e Sedativos/farmacologia , Receptores de GABA-B/fisiologia , Análise de Variância , Animais , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Reflexo/efeitos dos fármacos , AutoadministraçãoRESUMO
OBJECTIVE: This study examined the feasibility, safety, and efficacy of using tai chi for treating major depressive disorder. DESIGN: Thirty-nine Chinese Americans with major depressive disorder were randomized into a 12-wk tai chi intervention or a waitlisted control group in a 2:1 ratio. The key outcome measurement was the 17-item Hamilton Rating Scale for Depression. Positive response was defined as a decrease of 50% or more on the 17-item Hamilton Rating Scale for Depression, and remission was defined as a score of 7 or lower on the 17-item Hamilton Rating Scale for Depression. RESULTS: Of the participants (n = 39), 77% were women, and mean (SD) age was 55 (10) years. There were 26 (67%) participants in the tai chi intervention group and 13 (33%) in the control group. Of the participants in the tai chi group, 73% completed the intervention; no adverse events were reported. We observed trends toward improvement in the tai chi intervention group, compared with the control group, in positive treatment-response rate (24% vs. 0%) and remission rate (19% vs. 0%), although the differences in our small sample did not reach statistical significance. CONCLUSIONS: A randomized controlled trial of tai chi is feasible and safe in Chinese American patients with major depressive disorder. These promising pilot study results inform the design of a more definitive trial.
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Asiático , Transtorno Depressivo Maior/etnologia , Transtorno Depressivo Maior/reabilitação , Tai Chi Chuan/métodos , Adulto , Idoso , Transtorno Depressivo Maior/diagnóstico , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Satisfação do Paciente/estatística & dados numéricos , Projetos Piloto , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
Human T cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiologic agent for a number of disorders; the two most common pathologies include adult T cell leukemia (ATL) and a progressive demyelinating neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The neurologic dysfunction associated with HAM/TSP is a result of viral intrusion into the central nervous system (CNS) and the generation of a hyperstimulated host response within the peripheral and central nervous system that includes expanded populations of CD4+ and CD8+ T cells and proinflammatory cytokines/chemokines in the cerebrospinal fluid (CSF). This robust, yet detrimental immune response likely contributes to the death of myelin producing oligodendrocytes and degeneration of neuronal axons. The mechanisms of neurological degeneration in HAM/TSP have yet to be fully delineated in vivo and may involve the immunogenic properties of the HTLV-1 transactivator protein Tax. This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP.
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Sistema Nervoso Central/patologia , Infecções por HTLV-I/patologia , Doenças Musculares/patologia , Paraparesia Espástica Tropical/patologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , HumanosRESUMO
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a number of pathologic abnormalities, including adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The viral oncoprotein Tax has been implicated in the pathogenesis of these diseases. Recently, cell-free Tax was detected in the cerebrospinal fluid of HAM/TSP patients, implying that extracellular Tax may be relevant to neurologic disease. Additionally, the presence of a nuclear export signal within Tax and its active secretion has been demonstrated in vitro. However, the mechanism of Tax secretion remains to be established. Studies reported herein elucidate the process of Tax secretion and identify domains of Tax critical to its subcellular localization and secretion. Tax was shown to interact with a number of cellular secretory pathway proteins in both the model cell line BHK (baby hamster kidney)-21 and an HTLV-1-infected T cell line, C8166, physiologically relevant to HTLV-1-induced disease. Silencing of selected components of the secretory pathway affected Tax secretion, further confirming regulated secretion of Tax. Additionally, mutations in two putative secretory signals within Tax DHE and YTNI resulted in aberrant subcellular localization of Tax and significantly altered protein secretion. Together, these studies demonstrate that Tax secretion is a regulated event facilitated by its interactions with proteins of the cellular secretory pathway and the presence of secretory signals within the carboxyl-terminal domain of the protein.
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Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Sinais de Exportação Nuclear/fisiologia , Animais , Cricetinae , Produtos do Gene tax/líquido cefalorraquidiano , Produtos do Gene tax/genética , Inativação Gênica , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/líquido cefalorraquidiano , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/virologia , Paraparesia Espástica Tropical/líquido cefalorraquidiano , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/virologia , Estrutura Terciária de Proteína/fisiologia , Transporte Proteico/fisiologiaRESUMO
Protein kinase C (PKC) regulates a variety of neural functions, including ion channel activity, neurotransmitter release, receptor desensitization and differentiation. We have shown previously that mice lacking the epsilon-isoform of PKC (PKCepsilon) self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABA(A) receptors when compared with wild-type controls. The purpose of the present study was to examine involvement of PKCepsilon in GABA(A) receptor regulation of voluntary ethanol drinking. To address this question, PKCepsilon null-mutant and wild-type control mice were allowed to drink ethanol (10% v/v) vs. water on a two-bottle continuous access protocol. The effects of diazepam (nonselective GABA(A) BZ positive modulator), zolpidem (GABA(A) alpha1 agonist), L-655,708 (BZ-sensitive GABA(A) alpha5 inverse agonist), and flumazenil (BZ antagonist) were then tested on ethanol drinking. Ethanol intake (grams/kg/day) by wild-type mice decreased significantly after diazepam or zolpidem but increased after L-655,708 administration. Flumazenil antagonized diazepam-induced reductions in ethanol drinking in wild-type mice. However, ethanol intake by PKCepsilon null mice was not altered by any of the GABAergic compounds even though effects were seen on water drinking in these mice. Increased acute sensitivity to ethanol and diazepam, which was previously reported, was confirmed in PKCepsilon null mice. Thus, results of the present study show that PKCepsilon null mice do not respond to doses of GABA(A) BZ receptor ligands that regulate ethanol drinking by wild-type control mice. This suggests that PKCepsilon may be required for GABA(A) receptor regulation of chronic ethanol drinking.