NEUROBIOLOGY OF SPEEDBALL SELF-ADMINISTRATION

静脉注射毒品仍然是一个重大的公共卫生问题，已成为艾滋病传播的一个重要媒介。可卡因和海洛因的联合使用（快球）已被证明是治疗可卡因和海洛因滥用的一个重大挑战。这一应用提出了对快速球自我给药背后的大脑过程的研究。最近来自实验室的数据表明，与在药物滥用者中观察到的任何一种药物单独相比，快速球增强强化效应的潜在机制。自我给药可卡因/海洛因组合导致伏隔核（Nacc）细胞外液多巴胺（[DA]e）水平大幅增加，高于可卡因自我给药，而海洛因单独给药没有影响。本申请中提出的研究旨在验证海洛因或可卡因在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进行的，这种潜力是加速球增强强化作用的基础。实验将通过确定选择性烷基化对速球强化效果（渐进比例表）和自我给药阈值（固定比例表）的影响，初步评估这种潜力所需的基因座和阿片受体亚型。实验将通过确定选择性烷基化对速球强化效果（渐进比例表）和自我给药阈值（固定比例表）的影响，初步评估这种增强所必需的位点和阿片受体亚型。此外，可卡因与速球和Nacc [DA]e的剂量摄入关系将在整个剂量摄入曲线中进行评估。进一步的实验将确定，减弱海洛因对自我给药可卡因的强化效应和阈值降低效应的治疗是否也会减弱Nacc的增强作用[CA]。实验将通过向确定的脑区注射选择性GABA激动剂和拮抗剂并评估对自我给药阈值的影响，确定增强是否通过阿片受体影响GABA释放神经元；如果有效，则对Nacc [DA]e有效。此外，实验将评估在确定的脑区直接注射选择性阿片受体激动剂是否足以增强强化效果和降低可卡因自我给药的阈值。通过这种方式，可以确定这种增强的神经生物学机制。

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.