Amygdala TrkB in Amphetamine-Induced Learning

安非他明诱导学习中的杏仁核 TrkB

• 批准号: 6938925
• 负责人: FEI SHEN
• 金额: $ 2.5万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-29 至 2008-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938925
• 关键词: AMPA receptors; NMDA receptors; amphetamines; amygdala; association learning; behavior test; behavioral /social science research tag; biological signal transduction; brain derived neurotrophic factor; conditioning; glutamates; growth factor receptors; immunocytochemistry; laboratory rat; neural plasticity; neurotransmitter agonist; neurotransmitter transport; nontherapeutic iontophoresis; predoctoral investigator; protein structure function; protein tyrosine kinase; psychopharmacology

DESCRIPTION (provided by applicant): The persistence of addiction relates to the ability of drugs like amphetamine to cause permanent changes in brain regions that govern memories of emotionally significant events. One such brain region is the basolateral nucleus of the amygdala (blA). Normal learning and memory processes use neurotropic factors, like BDNF and its cognate trk-B receptor, and excitatory amino acids (EAA) acting at the NMDA and AMPA subtypes to alter synaptic strength and ultimately to change cell morphology. Neurons in the blA have a high expression level of each. We hypothesize that associative learning induced by amphetamine facilitates trk-B and EAA signaling in the blA. In a place conditioning paradigm, repeated administration of relative low does of amphetamine allow rats to learn to associate the environmental cues with drug. Amphetamine-induced motor function also can be progressively enhanced (termed sensitization). As both behaviors may model aspects of addiction, this paradigm will be used to test the three hypotheses of my specific aims. Hypothesis 1: Amphetamine-induced place preference will change the trk-B levels in the blA of rats. Expression of trk-B will be measured by immunohistochemistry in rats demonstrating place preference and/or motor sensitization. Hypothesis 2: Amphetamine-induced place preference will alter trk-B and EAA receptor function in blA. Neural firing will be measured electrophysiologically in vivo. Microiontophoresis of receptor agonists and antagonists will be used to measure receptor function. Hypothesis 3: Learning will be disrupted by infusion of the trk-B antagonist K-252a into blA. Rats will be surgically implanted with bilateral cannulae and K-252a will be infused and behavioral training will proceed as in Aims 1 and 2. Furthermore, a NMDA or AMPA agonist will be infused in an attempt to reinstate place preference.

描述（由申请人提供）： 成瘾的持续存在与安非他明等药物能够导致大脑区域发生永久性变化有关，这些区域负责管理情绪上重要事件的记忆。其中一个这样的大脑区域是杏仁核的基底外侧核（blA）。正常的学习和记忆过程使用神经营养因子（如 BDNF 及其同源 trk-B 受体）以及作用于 NMDA 和 AMPA 亚型的兴奋性氨基酸 (EAA) 来改变突触强度并最终改变细胞形态。 blA 中的神经元各自具有高表达水平。我们假设安非他明诱导的联想学习促进了 blA 中的 trk-B 和 EAA 信号传导。在场所调节范例中，重复给予相对低剂量的安非他明可以让老鼠学会将环境线索与药物联系起来。安非他明诱导的运动功能也可以逐渐增强（称为敏化）。由于这两种行为都可能模拟成瘾的各个方面，因此该范例将用于测试我的特定目标的三个假设。假设1：安非他明诱导的位置偏好会改变大鼠blA中trk-B的水平。 trk-B 的表达将通过免疫组织化学在大鼠中测量，显示位置偏好和/或运动敏化。假设 2：安非他明诱导的位置偏好会改变 blA 中的 trk-B 和 EAA 受体功能。将在体内通过电生理学方法测量神经放电。受体激动剂和拮抗剂的微离子电渗疗法将用于测量受体功能。假设 3：将 trk-B 拮抗剂 K-252a 输注到 blA 中会扰乱学习。将通过手术为大鼠植入双侧插管，并注入 K-252a，并按照目标 1 和 2 进行行为训练。此外，将注入 NMDA 或 AMPA 激动剂，以试图恢复位置偏好。