Amygdala TrkB in Amphetamine-Induced Learning

安非他明诱导学习中的杏仁核 TrkB

• 批准号: 7266945
• 负责人: FEI SHEN
• 金额: $ 0.54万
• 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 2007-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266945
• 关键词: 2-tyrosine; AMPA Receptors; Affect; Agonist; Amphetamines; Amygdaloid structure; Applications Grants; Behavior; Behavioral; Bilateral; Bion; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cannulas; Cell Nucleus; Cellular Morphology; Chromosome Pairing; Condition; Cues; Daily; Dose; Drug Addiction; Emotional; Emotions; Event; Excitatory Amino Acid Receptors; Excitatory Amino Acids; Exhibits; Fellowship; Fire - disasters; Glutamates; Growth; Hippocampus (Brain); Hour; Immunohistochemistry; Implant; Individual; Infusion procedures; Injection of therapeutic agent; Intake; K 252a; Learning; Long-Term Potentiation; Measures; Mediating; Memory; Modeling; Motor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Names; Neuronal Plasticity; Neurons; Pattern; Perception; Pharmaceutical Preparations; Phosphorylation; Process; Protein Tyrosine Kinase; Rattus; Relative (related person); Signal Transduction; Staining method; Stains; Synapses; Synaptic plasticity; Testing; Thinking; Tissues; Training; Tyrosine Kinase Inhibitor; Up-Regulation; Vertebral column; addiction; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; classical conditioning; conditioning; human TYRP1 protein; in vivo; interest; memory process; monoamine; motivational processes; motor learning; neurotropic; preference; psychostimulant; receptor; receptor function; relating to nervous system; research study; response; synaptogenesis; transmission process

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)： 成瘾的持久性与安非他明等药物导致大脑区域发生永久性变化的能力有关，这些区域管理着对重大情感事件的记忆。其中一个这样的大脑区域是杏仁基底外侧核(BLA)。正常的学习和记忆过程使用神经营养因子，如BDNF及其同源的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，最终改变细胞形态。BLA中的神经元每一个都有很高的表达水平。我们假设苯丙胺诱导的联想学习促进了BLA中Trk-B和EAA信号的传递。在一种地方条件作用范式中，反复给予相对较低剂量的苯丙胺，可以让大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，这个范例将被用来检验我的具体目标的三个假设。假设1：苯丙胺诱导的位置偏爱会改变大鼠脑白质中Trk-B的水平。Trk-B的表达将通过免疫组织化学方法在表现出位置偏爱和/或运动敏化的大鼠中进行检测。假设2：苯丙胺诱导的位置偏爱会改变BLA中trk-B和EAA受体的功能。神经放电将在活体内通过电生理学进行测量。受体激动剂和拮抗剂的微离子导入将用于测量受体功能。假设3：向BLA中注入trk-B拮抗剂K-252a将扰乱学习。大鼠将被手术植入双侧套管，K-252a将被注入，行为训练将像AIMS 1和2中那样进行。此外，将注入NMDA或AMPA激动剂试图恢复位置偏爱。