Lipase in Cocaine Cue Associations in the Amygdala

描述（由申请人提供）：吸毒成瘾是一个重大的健康问题，国家和地方。得克萨斯州被列为2003年至2004年可卡因相关死亡率最高的两个地点之一。2004年，3420万美国人（12岁及以上）报告终生使用可卡因。因此，可卡因成瘾的治疗是一个全国性的健康问题。对可卡因的渴望和可卡因滥用的复发是成瘾的一个特征，即使在长期戒断之后也会产生毁灭性的后果。触发这种复发的因素包括药物的存在，药物用具或与以前使用药物相关的环境。与基于线索的药物关联行为有关的大脑区域是杏仁核。由于线索可以在长期禁欲后引发渴望，因此长期使用可卡因可能会导致神经元可塑性的长期变化。这些变化可能包括某些突触的加强，这些突触可能是药物与吸毒发生的背景或环境之间联系的基础。这种改变可以通过类似于学习和记忆机制的神经递质传递的变化来介导。了解有助于线索和可卡因给药之间持久关联的机制是非常有价值的信息，因为数据将直接适用于治疗，这些治疗将专注于可卡因渴望和可卡因相关行为的靶向机制。这些研究最终将提供有助于治疗可卡因成瘾的成功率显着提高的疗法的信息。条件性位置偏爱（CPP）是一种测量线索诱导的可卡因联想行为的动物模型。我们已经表明，酶的活性，磷脂酶D（PLD），增加后可卡因诱导的条件性位置偏爱杏仁核。拟议的研究的总体目标是确定PLD的作用，在突触的变化，发生在线索诱导的可卡因联合行为，从慢性可卡因戒断。两个具体的目标解决这个目标：具体目标1，以表征杏仁核PLD活性和mGluR连接的PLD在CPP中的作用，具体目标2，以确定mGluR连接的PLD引起基底外侧到中央杏仁核通路中突触强度增加的机制。在这个建议中，我计划利用行为，电生理学和神经化学的方法来研究在杏仁核的动物表现出CPP和经历2周的慢性可卡因给药的戒断反应。

DESCRIPTION (provided by applicant): Drug addiction is a significant health problem nationally and locally. Texas was named as one of 2 sites with highest rate of cocaine-related deaths from 2003 to 2004. In 2004, 34.2 million Americans (12 and over) reported lifetime use of cocaine. Thus treatment of addiction to cocaine is a national health issue. Cocaine craving and relapse to cocaine abuse is a feature of addiction that has devastating consequences even after long periods of abstinence. Factors that trigger this relapse include the presence of drug, drug paraphenalia, or environment associated with previous use of the drug. A brain area implicated in cuebased drug associative behavior is the amygdala. Since cues can trigger craving after long periods of abstinence, long-term changes in neuronal plasticity due to chronic cocaine use are likely. These changes may include the strengthening of certain synapses which may underlie the association between the drug and the context or environment in which drug-taking occurred. Such modifications can be mediated through changes in glutamatergic transmission similar to learning and memory mechanisms. Understanding the mechanisms contributing to the lasting association between the cues and cocaine administration is extremely valuable information since data will be directly applicable to treatments that will focus on targeting mechanisms underlying cocaine-craving and cocaine-associative behaviors. These studies would ultimately provide information that contributes to therapies which produce significantly higher success rates in treating cocaine addiction. Conditioned place preference (CPP) is an animal model measuring cue-induced cocaine associative behavior. We have shown that the activity of the enzyme, phospholipase D (PLD), is increased in the amygdala after cocaine-induced conditioned place preference. The overall goal of the proposed research is to determine the role of PLD in the synaptic changes that occur in cue-induced cocaine associative behavior during withdrawal from chronic cocaine. Two specific aims address this goal: specific aim 1, to characterize the role of amygdala PLD activity and mGluR-linked PLD in CPP and specific aim 2, to determine the mechanism by which the mGluR-linked PLD causes an increase in synaptic strength in the basolateral to central amygdala pathway. In this proposal, I plan to utilize behavioral, electrophysiological, and neurochemical approaches to study glutamatergic transmission in the amygdala of animals exhibiting CPP and undergoing 2 week withdrawal from chronic cocaine administration.