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; 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）： 成瘾的持久性与苯丙胺这样的药物在控制情绪重要事件的记忆的大脑区域中永久变化的能力有关。这样的大脑区域之一是杏仁核（BLA）的基底外侧核。正常的学习和记忆过程使用神经性因子，例如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）以改变突触强度并最终改变细胞形态。 BLA中的神经元具有高表达水平。我们假设苯丙胺引起的联想学习促进了BLA中的TRK-B和EAA信号传导。在调节范式的地方，反复给予相对低的苯丙胺使大鼠学会将环境线索与药物联系起来。苯丙胺诱导的运动功能也可以逐步增强（称为敏化）。由于两种行为都可能模拟成瘾的各个方面，因此该范式将用于测试我特定目标的三个假设。假设1：苯丙胺诱导的位置偏好将改变大鼠BLA的TRK-B水平。 TRK-B的表达将通过大鼠的免疫组织化学来测量，证明位置偏爱和/或运动敏化。假设2：苯丙胺诱导的位置偏好将改变BLA中的TRK-B和EAA受体功能。神经发射将在体内进行电生理测量。受体激动剂和拮抗剂的微孔粒子将用于测量受体功能。假设3：将TRK-B拮抗剂K-252A输注到BLA中会破坏学习。大鼠将用双侧套管进行外科手术植入，并且将注入K-252A，而行为训练将如AIMS 1和2中进行。此外，将注入NMDA或AMPA激动剂，以尝试重新定局偏好。