NEUROBIOLOGY OF SPEEDBALL SELF-ADMINISTRATION

快速球自我管理的神经生物学

• 批准号: 6702538
• 负责人: JAMES E SMITH
• 金额: $ 24.54万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-20 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702538
• 关键词: cocaine; dopamine; drug abuse; gamma aminobutyrate; heroin; laboratory rat; membrane potentials; neurobiology; nucleus accumbens; opioid receptor; reinforcer; self medication; substance abuse related behavior

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.

静脉吸毒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。事实证明，可卡因和海洛因的联合使用（快速球）对于治疗可卡因和海洛因滥用来说是一个重大挑战。该申请提出了对快速球自我管理背后的大脑过程的研究。 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，速度球增强增强效果的潜在机制。自我给予可卡因/海洛因组合导致伏隔核（Nacc）中多巴胺（[DA]e）的细胞外液水平大幅增加，高于自我给予可卡因，而单独自我给予海洛因则没有效果。本申请中提出的研究旨在检验以下假设：海洛因或可卡因对 Nacc 中 [DA]e 的升高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果的基础。实验将首先通过确定选择性烷基化对速度球的增强功效（采用渐进比例方案）和自我给药阈值（采用固定比例方案）的影响来评估这种潜力所需的基因座和阿片受体亚型。实验将首先通过确定选择性烷基化对速度球的增强功效（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基因座和阿片受体亚型。此外，将在整个剂量摄入曲线中评估可卡因、速球和 Nacc [DA]e 的剂量摄入关系之间的关联。其他实验将确定减弱海洛因对自我施用可卡因的增强功效和阈值降低作用的治疗是否也会减弱 Nacc [CA]e 的增强作用。实验将通过将选择性 GABA 激动剂和拮抗剂注射到确定的大脑区域并评估对自我给药阈值的影响，确定增强作用是否是通过阿片受体影响 GABA 释放神经元；如果有效，则使用 Nacc [DA]e。此外，实验将评估将选择性阿片受体激动剂直接注射到确定的大脑区域是否足以增强增强功效并降低可卡因自我给药的阈值。以这种方式，可以确定这种增强的神经生物学机制。