NUCLEUS ACCUMBENS /VENTRAL PALLIDUM /COCAINE /SPEEDBALL

该子项目4将建立在上一个资助期的研究结果基础上：1）对可卡因和速度球期间延髓核（NAcc）和腹侧苍白球（VP）之间的相互联系进行广泛分析（可卡因/海洛因混合）自我给药; 2）将药物自我调节的新模型给药以表征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。第一个具体的目标将在体内微透析的可卡因和速度球的神经化学作用的NAcc和VP中的D2受体的作用的特点。第二个具体目标将描述可卡因，海洛因和速度球的相对疗效与一个离散的试验模型的自我管理，显示出显着的承诺，调查的神经生物学事件的基础上，从药物使用的过渡到失去控制，药物滥用的特点。将评估可卡因、海洛因和快球在昼夜节律或非昼夜节律中维持自我给药的能力 随着离散试验间隔的减小，将评估食品强化反应 同时作为另一种失去控制的措施。将使用微透析来确定特定目标1的结果是否在该过度药物使用模型中发生改变。第三个具体目标将表征NAcc和VP中D2受体在可卡因、海洛因或快球的离散试验自我给药中的作用。NAcc、VP或这两个区域中的D2受体将在具有离散试验访问的自我施用可卡因、海洛因或快球的大鼠中耗尽。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。这些大脑区域将被评估基因 使用实时RT-PCR对相关鉴定的靶标进行表达。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体外伏安法。此外，将从项目0011接收脑组织，用于使用实时RT-PCR进行靶向基因表达研究，此时使用特定目的2和3中的动物组织鉴定相关靶点。所提出的实验将有望显着增加我们的理解NAcc-VP相互作用的药物自我管理和药物使用的过渡到药物成瘾。

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.