Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen

拟议的职业发展计划旨在为专业人员提供独特的技能和经验，以 满足成为一名富有成效的独立研究员的短期目标和成为一名 对了解和治疗药物滥用障碍做出了重要贡献。该计划将是 这项研究是在肯塔基大学进行的，这是一所在跨学科药物滥用方面有着丰富历史的机构 研究。PI将由Michael Bardo博士指导，Greg Gerhardt博士共同指导， 分别是神经精神药理学和神经化学方面的专家。该计划建议使用酶- 基于微电极阵列发现亚秒强直/相皮质边缘谷氨酸的作用 奖励相关线索和可卡因的激励显著/价值归因的个体差异释放 在临床前大鼠模型中的强化。当刺激可靠地预测奖励时，一些动物将 刺激的激励价值，并因此会接近和接触它(手势跟踪器)；其他动物使用 刺激作为即将到来的奖励的简单信号，因此将接近奖励将进入的容器 被传递(目标追踪器)。最近，有研究表明，手势和目标跟踪方面的差异是 与寻求新奇、冲动、对可卡因强化的初始脆弱性和复发脆弱性有关。 除了大脑皮质边缘的多巴胺，已知刺激奖赏学习和滥用药物也会改变 皮质边缘谷氨酸信号转导。总体上提出的假设是，激励价值的差异 归因是通过线索暴露时不同的皮质边缘谷氨酸释放来调节的；这 然后，重复给药加剧了不同的释放，导致不同的释放 药物滥用、脆弱性和复发。具体目标1将决定是否逐秒主音/相位 在手势跟踪动物和目标跟踪动物中，谷氨酸信号受到与食物相关的线索的不同影响。 特异性靶点2将确定多巴胺能受体功能在SIGN-/Goal-表达中的作用 跟踪和潜在的强/相谷氨酸信号。具体目标3将决定一秒一秒地 手势和目标跟踪动物的强直和时相谷氨酸能信号变化不同于 反复使用可卡因自我注射。然后，特定目标4将确定多巴胺能受体的作用 在手势跟踪器和目标跟踪器中对可卡因自我给药和强/相谷氨酸信号的作用。 总而言之，这些结果将提供对强/相谷氨酸信号在刺激中的作用的洞察。 奖励学习、奖励相关刺激的激励价值归因和可卡因强化，而 由两方面的专家为PI提供独特的神经精神药理学和神经化学培训 菲尔兹。

The proposed career development plan is designed to provide the PI with a unique skill set and experience to meet the short-term goal of becoming a productive, independent researcher and long-term goal of becoming a significant contributor to the understanding and treatment of substance abuse disorders. The plan will be carried out at the University of Kentucky, an institution with a rich history of interdisciplinary substance abuse research. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt, established experts in neuropsychopharmacology and neurochemistry, respectively. The plan proposes to use enzyme- based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamate release in individual differences in incentive salience/value attribution to reward-related cues and cocaine reinforcement in a preclinical rat model. When a stimulus reliably predicts reward, some animals attribute incentive value to the stimulus, and thus will approach and contact it (sign-trackers); other animals use the stimulus as a simple signal of forthcoming reward, and thus will approach the receptacle into which reward will be delivered (goal-trackers). Recently, it has been demonstrated that differences in sign and goal tracking are related to novelty seeking, impulsivity, initial vulnerability to cocaine reinforcement, and relapse vulnerability. In addition to mesocorticolimbic dopamine, stimulus-reward learning and drugs of abuse are known to alter mesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive value attribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; this differential release is then exacerbated by repeated cocaine self-administration, giving rise to differential substance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasic glutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals. Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal- tracking, and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially with repeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptor function on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers. Collectively, these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus- reward learning, incentive value attribution to reward-associated stimuli, and cocaine reinforcement, while providing the PI with unique training in neuropsychopharmacology and neurochemistry by experts in both fields.