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: 8039452
• 负责人: YOUSSEF SARI
• 金额: $ 23.59万
• 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/8039452
• 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; 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. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to investigate the role of glutamate transporter, a neurotransmitter transporter, in alcohol dependence. This chemical transporter plays an important role in alcohol-drinking behavior. From this study, we aim to provide ample information about the role of this transporter in the reduction of alcohol consumption and hope to pave the path toward potential therapeutic targets for alcohol dependence.

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预防和/或治疗这些主要健康问题的干预措施。新出现的证据表明，乙醇和药物依赖的许多方面涉及谷氨酸传输的变化。由于谷氨酸转运蛋白1（GLT 1）负责摄取大部分细胞外谷氨酸，我们测试了这一假设，即增加GLT 1功能将减弱乙醇消耗的酒精偏好大鼠（P大鼠）。在P大鼠长期暴露于自由选择的EtOH（15和30%）五周后，给它们施用头孢曲松（i. p.），一种已知能提高GLT 1表达的β-内酰胺抗生素，连续5天。我们发现，头孢曲松治疗的P大鼠表现出减少乙醇摄入量的治疗期间相比，接受生理盐水车辆的大鼠。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药物（GPI-1046和MS-153）已知激活GLT 1在衰减的EtOH摄入在两个不同的时间点的慢性EtOH暴露在P大鼠的长期影响。我们还将研究GLT 1激活对Wistar大鼠乙醇饮酒行为的影响，作为比较对照组。我们在目标1中的工作假设是，通过上调或激活，GLT 1功能的增加减弱了P和Wistar大鼠中的EtOH消耗。我们将采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，停药期间GLT 1功能的增加将减少动物再次暴露于EtOH时的复发样行为。最低测试剂量的头孢曲松（25 mg/kg）未显示GLT 1表达增加，也有效减少EtOH摄入。这些发现表明，头孢曲松可能对GLT 1有其他药理学作用，或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变化）。因此，我们在目标3中提出确定涉及头孢曲松或GPI-1046上调GLT 1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的磷酸化激活GLT 1功能。从这个提议中产生的发现将提供有关GLT 1在调节EtOH消耗中的作用的充分信息，并将为寻找酒精成瘾的潜在治疗靶点铺平道路。 公共卫生关系：本研究的目的是探讨谷氨酸转运体（一种神经递质转运体）在酒精依赖中的作用。这种化学转运蛋白在饮酒行为中起着重要作用。从这项研究中，我们的目标是提供有关这种转运蛋白在减少酒精消耗中的作用的充分信息，并希望为酒精依赖的潜在治疗靶点铺平道路。