NUCLEUS ACCUMBENS /VENTRAL PALLIDUM /COCAINE /SPEEDBALL

伏核/腹侧苍白球/可卡因/SPEEDBALL

基本信息

批准号：
6695727
负责人：
JAMES E SMITH
金额：
$ 10.47万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2008-11-30
项目状态：
已结题

项目摘要

This subproject 4 will build upon findings from the previous funding period to: 1) conduct an extensive analysis of the intercommunication between nucleus accumbens (NAcc) and ventral pallidum (VP) during cocaine and speedball (cocaine/heroin combinations) self-administration; 2) incorporate novel models of drug self-administration to characterize the transition from drug use to drug abuse which may more closely mimic the addictive processes in humans. The investigators have used 6-hydroxy-dopamine (6-OHDA) and D2 receptor alkylation to reveal differences in cocaine and speedball self-administration in NAcc and VP. These data, and recent literature, suggest important differences between NAcc and VP in the maintenance of drug self-administration. The first specific aim will characterize the role of D2 receptors in the NAcc and VP in the neurochemical effects of cocaine and speedball using in vivo microdialysis. The second specific aim will characterize the relative efficacy of cocaine, heroin and speedball with a discrete trial model of self-administration that shows significant promise for the investigation of the neurobiological events that underlie the transition from drug use to the loss of control that characterizes drug abuse. Cocaine, heroin and speedball will be evaluated for their abilities to maintain self-administration in a circadian or non-circadian manner as the discrete trial interval is decreased. Food reinforced responding will be evaluated concurrently as another measure of the loss of control. Microdialysis will be used to determine if findings from Specific Aim 1 are altered in this model of excessive drug use. The third specific aim will characterize the role of D2 receptors in NAcc and VP in the discrete trial self-administration of cocaine, heroin or speedball. D2 receptors in either NAcc, VP or both regions will be depleted in rats self-administering cocaine, heroin or speedball with discrete trial access. The effects on pattern of self-administration will be assessed to determine if D2 receptor depletion will restore circadian patterns of drug intake and/or reverse the effects on disruption of food-maintained responding. These brain regions will then be assessed for gene expression using real-time RT-PCR for relevant identified targets. Brain tissue will be shared with subprojects 0001, 0008 and 0011 for receptor G-protein coupling studies, connexin gene expression and for ex vivo voltammetry. In addition, brain tissue will be received from Project 0011 for targeted gene expression studies using real-time RT-PCR when relevant targets are identified using the tissue rom animals in specific aims 2 and 3. The proposed experiments will hopefully add significantly to our understanding of NAcc - VP interactions in drug self-administration and in the transition from drug use to drug addiction.

该子项目 4 将建立在上一个资助期的研究结果的基础上：1）对可卡因和快速球（可卡因/海洛因组合）自我给药期间伏隔核（NAcc）和腹侧苍白球（VP）之间的相互交流进行广泛分析； 2）纳入药物自我给药的新模型来描述从药物使用到药物滥用的转变，这可能更接近地模拟人类的成瘾过程。研究人员使用 6-羟基多巴胺 (6-OHDA) 和 D2 受体烷基化来揭示 NAcc 和 VP 中可卡因和快速球自我给药的差异。这些数据和最近的文献表明 NAcc 和 VP 在维持药物自我给药方面存在重要差异。第一个具体目标是利用体内微透析来表征 NAcc 和 VP 中 D2 受体在可卡因和快速球的神经化学作用中的作用。第二个具体目标将通过自我给药的离散试验模型来表征可卡因、海洛因和速球的相对功效，该模型对于研究从吸毒到失去控制的转变的神经生物学事件具有重大前景。虐待。将评估可卡因、海洛因和速球在昼夜节律或非昼夜节律中维持自我给药的能力方式随着离散试验间隔的减少而变化。将评估食物强化反应同时作为失控的另一种衡量标准。微透析将用于确定特定目标 1 的结果在过度药物使用模型中是否发生改变。第三个具体目标将描述 NAcc 和 VP 中 D2 受体在可卡因、海洛因或快速球自我给药的离散试验中的作用。在大鼠自我施用可卡因、海洛因或快速球并进行离散试验时，NAcc、VP 或两个区域中的 D2 受体将被耗尽。将评估对自我给药模式的影响，以确定 D2 受体耗竭是否会恢复药物摄入的昼夜节律模式和/或逆转对食物维持反应破坏的影响。然后将评估这些大脑区域的基因使用实时 RT-PCR 来表达相关已识别的靶标。脑组织将与子项目 0001、0008 和 0011 共享，用于受体 G 蛋白偶联研究、连接蛋白基因表达和离体伏安法。此外，当使用特定目标 2 和 3 中的动物组织确定相关目标时，将从 0011 项目获得脑组织，用于使用实时 RT-PCR 进行靶向基因表达研究。所提出的实验有望显着增进我们的理解NAcc - VP 在药物自我给药以及从吸毒到吸毒成瘾的转变中的相互作用。