Amygdala TrkB in Amphetamine-Induced Learning

描述（由申请人提供）： 成瘾的持续性与安非他明等药物引起大脑区域永久性变化的能力有关，这些区域控制着对情感重要事件的记忆。其中一个这样的脑区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中的神经元具有各自的高表达水平。我们推测，苯丙胺诱导的联想学习促进blA中的trk-B和EAA信号。在一个地方条件反射范例中，反复给予相对低剂量的安非他明使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（称为致敏）。由于这两种行为都可能模拟成瘾的各个方面，因此这个范式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blA中trk-B的水平。将通过免疫组织化学法测量显示位置偏好和/或运动致敏的大鼠中trk-B的表达。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。神经放电将在体内进行电生理学测量。受体激动剂和拮抗剂的微离子电渗将用于测量受体功能。假设3：将trk-B拮抗剂K-252 a输注到blA中会破坏学习。将通过手术向大鼠植入双侧插管，并输注K-252 a，并按照目的1和2进行行为训练。此外，将输注NMDA或AMPA激动剂以试图恢复位置偏好。

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.