Benzodiazepine-Induced Glutamate Receptor Plasticity

苯二氮卓诱导的谷氨酸受体可塑性

• 批准号: 6919745
• 负责人: ELIZABETH I TIETZ
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919745
• 关键词: anxiety; benzodiazepines; drug withdrawal; electron microscopy; excitatory aminoacid; flurazepam; glutamate receptor; immunocytochemistry; laboratory rat; light microscopy; neural plasticity

DESCRIPTION (provided by applicant): The neurophysiological mechanisms underlying withdrawal syndromes reflecting physical dependence on a variety of drugs of abuse, including the benzodiazepines (BZs), are unknown. Using a well-established rat model of chronic BZ treatment, we have identified changes in hippocampal excitatory amino acid receptors temporally associated with anxiety-like behavior, a sign of withdrawal. CA1 neuron changes include increases in alpha-amino-3-hydroxy-5-methyl-4-isozaxolepropionic acid receptor (AMPAR) current amplitude and conductance, and increases in AMPAR binding and GluR1 subunit levels. When AMPAR currents increase, N-methyl-D-aspartate receptor (NMDAR)-evoked currents, NMDA efficacy and NR2B subunit levels are reduced. NMDA antagonist treatment during withdrawal reverses NMDAR down regulation, allowing more prolonged expression of anxiety-like behavior. AMPAR antagonist treatment prevents subsequent AMPAR upregulation. These findings suggest that enhanced AMPAR function contributes to BZ-induced withdrawal through NMDAR-dependent hippocampal pathways, and are reminiscent of well-described mechanisms underlying activity-dependent plasticity of hippocampal excitatory synapses. Similar mechanisms may be involved in behavioral plasticity during BZ withdrawal. The working hypothesis is that localized remodeling of hippocampal CA1 neuron excitatory synapses is a central feature underlying BZ physical dependence, expressed as withdrawal-induced anxiety-like behavior, and has essential characteristics analogous to those associated with activity-dependent synaptic plasticity. Three specific hypotheses focus on the subunit dependence of the functional and structural alterations that occur at CA1 neuron EAAR synapses after withdrawal from 1-week flurazepam treatment. AMPA and NMDAR function will be studied at selected time-points after drug removal, when anxiety-like behavior is expressed, using whole-cell and outside-out patch techniques in hippocampal slices and acutely dissociated CA1 neurons. The first aim will be to explore AMPAR channel properties using GluR1 subunit-selective neurophysiological and pharmacological tools. The second aim will use a similar approach to study the NR2B-subunitdependence of decreased NMDAR function at CA1 synapses. The third aim is to use light microscopic and electron microscopic immunohistochemical approaches to investigate the structural changes in AMPARs and NMDARs at CA1 synapses that contribute to changes in hippocampal excitatory function and to anxiety-like behavior. Rational approaches to the treatment of physical dependence on drugs of abuse can emerge from a better understanding of the neurophysiological mechanisms underlying withdrawal phenomena.

描述（由申请方提供）：反映对多种滥用药物（包括苯二氮卓类（BZ））的身体依赖性的戒断综合征的神经生理学机制尚不清楚。使用一个完善的大鼠模型的慢性BZ治疗，我们已经确定了海马兴奋性氨基酸受体的变化与焦虑样行为，一个信号的撤退时间。CA 1神经元变化包括α-氨基-3-羟基-5-甲基-4-异唑丙酸受体（AMPAR）电流幅度和电导增加，以及AMPAR结合和GluR 1亚单位水平增加。当AMPAR电流增加时，N-甲基-D-天冬氨酸受体（NMDAR）诱发的电流、NMDA功效和NR 2B亚基水平降低。戒断期间的NMDA拮抗剂治疗逆转NMDAR下调，允许焦虑样行为更长时间的表达。AMPAR拮抗剂治疗防止随后的AMPAR上调。这些研究结果表明，增强AMPAR功能有助于BZ诱导的戒断通过NMDAR依赖性海马通路，并让人联想到海马兴奋性突触的活动依赖性可塑性的基础机制。类似的机制可能涉及行为可塑性在BZ撤退。工作假设是，海马CA 1神经元兴奋性突触的局部重塑是BZ物理依赖的核心特征，表现为戒断诱导的焦虑样行为，并具有与活动依赖性突触可塑性相关的基本特征。三个具体的假设集中在亚基依赖的功能和结构的变化，发生在CA 1神经元EAAR突触后退出1周的泮治疗。将在药物去除后的选定时间点研究AMPA和NMDAR功能，此时表达焦虑样行为，在海马切片和急性分离的CA 1神经元中使用全细胞和外向补丁技术。第一个目标将是探索AMPAR通道特性使用GluR 1亚基选择性神经生理学和药理学工具。第二个目标将使用类似的方法来研究NR 2B-亚基依赖性的减少NMDAR功能在CA 1突触。第三个目的是使用光镜和电镜免疫组织化学方法来研究CA 1突触的AMPAR和NMDAR的结构变化，这些结构变化有助于海马兴奋功能和焦虑样行为的变化。对药物滥用的身体依赖性的合理治疗方法可以从更好地理解戒断现象背后的神经生理学机制中产生。