Lipase in Cocaine Cue Associations in the Amygdala

描述（由申请人提供）：吸毒成瘾是国家和地方的一个重大健康问题。从2003年到2004年，德克萨斯州被列为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，治疗可卡因成瘾是一个全国性的健康问题。对可卡因的渴望和对可卡因滥用的复发是成瘾的一个特征，即使在长时间的戒断之后也会产生毁灭性的后果。引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。与基于线索的药物联想行为有关的大脑区域是杏仁核。由于线索可以在长时间的戒断后引发渴望，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发生吸毒的背景或环境之间联系的基础。这种改变可以通过谷氨酸传递的变化来介导，类似于学习和记忆机制。了解促成线索和可卡因给药之间持久联系的机制是非常有价值的信息，因为数据将直接适用于将重点放在针对可卡因渴望和可卡因相关行为的潜在机制的治疗。这些研究最终将提供有助于提高治疗可卡因成瘾成功率的治疗方法的信息。条件位置偏好（CPP）是一种测量线索诱导的可卡因联想行为的动物模型。我们已经证明，在可卡因诱导的条件位置偏好后，杏仁核中磷脂酶D （PLD）的活性增加。拟议研究的总体目标是确定PLD在慢性可卡因戒断期间线索诱导的可卡因联想行为中发生的突触变化中的作用。两个特定目标解决了这一目标：特定目标1，表征杏仁核PLD活性和mglur连接的PLD在CPP中的作用；特定目标2，确定mglur连接的PLD导致杏仁核基底外侧到中央通路突触强度增加的机制。在这个提案中，我计划利用行为学、电生理学和神经化学方法来研究CPP动物的杏仁核中谷氨酸能的传递，这些动物已经停止了2周的慢性可卡因治疗。

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.