NEUROBIOLOGY OF SPEEDBALL SELF-ADMINISTRATION

静脉注射毒品仍然是一个主要的公共卫生问题，已成为艾滋病传播的重要媒介。可卡因和海洛因的混合使用（快球）已被证明是可卡因和海洛因滥用治疗的一个重大挑战。本申请提出调查的大脑过程背后的速度球自我管理。 实验室的最新数据表明，与在药物滥用者中观察到的单独药物相比，快速球的增强作用有一种潜在的机制。可卡因/海洛因组合的自我给药导致脑桥核（Nacc）中多巴胺（[DA] e）的细胞外液水平比可卡因自我给药的细胞外液水平大幅度增加，而海洛因单独自我给药没有影响。本申请中提出的研究旨在验证以下假设：海洛因或可卡因在Nacc中升高[DA] e的增强作用可能是通过GABA神经元上的阿片受体，并且这种潜力是速度球增强增强效应的基础。实验最初将通过确定选择性烷基化对速度球强化疗效（采用渐进比例方案）和自我给药阈值（采用固定比例方案）的影响来评估这种潜力所需的位点和阿片受体亚型。实验最初将通过确定选择性烷基化对速度球的强化功效（采用渐进比例方案）和自我给药阈值（采用固定比例方案）的影响来评估这种增强所需的位点和阿片受体亚型。此外，将在整个剂量-摄入曲线中评估可卡因和快球的剂量摄入关系与Nacc [DA] e之间的相关性。另外的实验将确定减弱海洛因对自我施用的可卡因的增强功效和阈值降低作用的增强的处理是否也减弱Nacc [CA] e的增强。实验将通过将选择性GABA激动剂和拮抗剂注射到确定的脑区并评估对自我给药阈值的影响，以及如果有效，对Nacc [DA] e的影响，来确定增强作用是否是通过影响GABA释放神经元的阿片受体。此外，实验将评估是否选择性阿片受体激动剂直接注射到确定的大脑区域是足以提高可卡因自我管理的增强功效和较低的阈值。通过这种方式，可以确定这种增强作用的神经生物学机制。

Intravenous drug use continues to be a major public health problem which has become a significant vector for the spread of AIDS. The combined use cocaine and heroin (speedball) has proven to be a significant challenge for the treatment of cocaine and heroin abuse. This application proposes investigation of the brain processes underlying speedball self- administration. Recent data from the laboratory suggests a potential mechanism for the enhance reinforcing effects of speedball compared to either drug alone that is observed in drug abusers. The self-administration of cocaine/heroin combinations resulted in large increases in the extracellular fluid levels of dopamine ([DA]e) in the nucleus accumbens (Nacc) above that with cocaine self-administration, while heroin self- administered alone has no effect. The research proposed in this application is designed to test the hypothesis that the potentiation of heroin of cocaine's elevation of [DA]e in the Nacc are through opioid receptors perhaps on GABA neurons and this potential is the basis of the enhanced reinforcing effects of speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potential by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potentiation by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. In addition, the association between the dose intake relationship for cocaine and speedball and Nacc [DA]e will be assessed throughout the dose-intake curve. Additional experiments will determine if treatments that attenuate the potentiation of reinforcing efficacy and threshold lowering effects of heroin on self-administered cocaine also attenuate the potentiation of Nacc [CA]e. Experiments will determine whether the potentiation is through opioid receptors that impact GABA releasing neurons by injecting selective GABA agonists and antagonists into identified brain regions and assessing effects on self-administration thresholds; and, if effective, on Nacc [DA]e. In addition, experiments will assess whether direct injections of selective opioid receptor agonists into identified brain regions is sufficient to enhance the reinforcing efficacy and lower thresholds for cocaine self-administration. In this manner, the neurobiological mechanisms of this potentiation can be determined.