The role of GLT1 in the modulation of alcohol-drinking behavior in P rats.

GLT1 在 P 大鼠饮酒行为调节中的作用。

• 批准号: 8461673
• 负责人: YOUSSEF SARI
• 金额: $ 21.94万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461673
• 关键词: Alcohol consumption; Alcohol dependence; Alcohols; Animals; Attenuated; Behavior; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain region; Carrier Proteins; Ceftriaxone; Chemicals; Chronic; Cocaine; Consumption; Control Groups; Dependence; Dose; Drug Addiction; Ethanol; Excision; Extracellular Fluid; Family; Glutamate Transporter; Glutamates; Glutathione; Goals; Health; Individual; Intake; Legal patent; Long-Term Effects; MS-153; Microdialysis; Modeling; Molecular; Molecular Mechanisms of Action; Monobactams; NF-kappa B; Neurobiology; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Play; Prefrontal Cortex; Prevention; Principal Investigator; Proteins; Proteomics; Public Health; Rattus; Regulation; Relapse; Rewards; Role; Saline; Self Administration; Signal Pathway; Sodium; System; Testing; Therapeutic; Time; Treatment Effectiveness; Up-Regulation; Wistar Rats; Withdrawal; Work; alcohol preferring rats; attenuation; base; deprivation; dihydrokainate; drinking behavior; extracellular; human FRAP1 protein; male; neurochemistry; oxidation; prevent; programs; public health relevance; therapeutic target; therapy development; transmission process; treatment duration; uptake

DESCRIPTION (provided by applicant): Alcohol (EtOH) abuse and dependence continue to be significant public health problems. Thus, a better understanding of their neurobiology will facilitate the development of interventions targeting prevention and/or treatment of these major health issues. Emerging evidence indicates that many aspects of EtOH and drug dependence involve changes in glutamate transmission. Because glutamate transporter 1 (GLT1) is responsible for the uptake of the majority of extracellular glutamate, we tested the hypothesis that increased GLT1 function would attenuate EtOH consumption in alcohol-preferring rats (P rats). After P rats had been chronically exposed to a free choice of EtOH (15 and 30%) for five weeks, they were administered ceftriaxone (i.p.), a beta-lactam antibiotic known to elevate GLT1 expression, for five consecutive days. We found that ceftriaxone-treated P rats showed a reduction in EtOH intake for the duration of treatment as compared to rats that received a saline vehicle. The long-term effects of ceftriaxone, however, are unknown. Here, we will test the long-term effects of ceftriaxone and other drugs (GPI-1046 and MS-153) known to activate GLT1 in the attenuation of EtOH intake at two different time points of chronic EtOH exposure in P rats. We will also investigate the effects of GLT1 activation in EtOH-drinking behavior in Wistar rats as comparison control groups. Our working hypothesis in aim 1 is that an increase in GLT1 function, via up- regulation or activation, attenuates EtOH consumption in both P and Wistar rats. The EtOH deprivation effect, which we will employ, has been used to assess relapse-like behavior in P rats. In aim 2, our working hypothesis is that an increase in GLT1 function during withdrawal periods will reduce relapse-like behavior when animals are re-exposed to EtOH. The lowest tested dose of ceftriaxone (25 mg/kg), which did not show an increase in GLT1 expression, was also effective in reducing EtOH intake. These findings suggest that ceftriaxone may have other pharmacological effects on GLT1 or may act by another mechanism (a functional increase may involve a change in one of several mechanisms). Thus, we propose in aim 3 to determine the signaling pathways involving ceftriaxone or GPI-1046 in up-regulation of GLT1 expression. Moreover, we aim to determine the molecular mechanisms of action of ceftriaxone, GPI-1046 and MS-153, which may involve activation of GLT1 function through phosphorylation of key proteins. The findings generated from this proposal will provide ample information about the role of GLT1 in the regulation of EtOH consumption and will pave the path toward finding a potential therapeutic target for alcohol addiction.

描述（由申请人提供）：酒精 (EtOH) 滥用和依赖仍然是重大的公共卫生问题。因此，更好地了解他们的神经生物学将有助于制定针对这些主要健康问题的预防和/或治疗的干预措施。新出现的证据表明，乙醇和药物依赖的许多方面都涉及谷氨酸传输的变化。由于谷氨酸转运蛋白 1 (GLT1) 负责大多数细胞外谷氨酸的摄取，因此我们测试了以下假设：增加 GLT1 功能会减少嗜酒大鼠 (P 大鼠) 的 EtOH 消耗。 P 大鼠长期暴露于自由选择的 EtOH（15% 和 30%）五周后，连续五天给予头孢曲松（腹腔注射），这是一种已知可提高 GLT1 表达的 β-内酰胺抗生素。我们发现，与接受盐水载体的大鼠相比，头孢曲松治疗的 P 大鼠在治疗期间显示出乙醇摄入量减少。然而，头孢曲松的长期影响尚不清楚。在这里，我们将测试头孢曲松和其他已知可激活 GLT1 的药物（GPI-1046 和 MS-153）在 P 大鼠慢性 EtOH 暴露的两个不同时间点对 EtOH 摄入量减弱的长期影响。我们还将研究 GLT1 激活对 Wistar 大鼠乙醇饮酒行为的影响（作为对照组）。我们在目标 1 中的工作假设是，通过上调或激活，GLT1 功能的增加会减少 P 和 Wistar 大鼠的 EtOH 消耗。我们将使用乙醇剥夺效应来评估 P 大鼠的复发样行为。在目标 2 中，我们的工作假设是，戒断期间 GLT1 功能的增强将减少动物重新暴露于 EtOH 时的复发样行为。头孢曲松的最低测试剂量（25 mg/kg）并未显示 GLT1 表达增加，但也能有效减少 EtOH 摄入量。这些发现表明，头孢曲松可能对 GLT1 具有其他药理作用，或者可能通过另一种机制起作用（功能增加可能涉及几种机制之一的改变）。因此，我们在目标 3 中建议确定涉及头孢曲松或 GPI-1046 上调 GLT1 表达的信号通路。此外，我们的目标是确定头孢曲松、GPI-1046 和 MS-153 的分子作用机制，这可能涉及通过关键蛋白磷酸化激活 GLT1 功能。该提案产生的结果将提供有关 GLT1 在调节 EtOH 消耗中的作用的充足信息，并将为寻找酒精成瘾的潜在治疗靶点铺平道路。