Neurobiology of Speedball Self-administration

描述（由申请人提供）：静脉注射吸毒仍然是一个主要的公共卫生问题，是艾滋病传播的一个重要媒介，可卡因和阿片类激动剂的共同使用正在增加，最近显示会降低成功治疗结果的可能性。这一应用建议继续研究可卡因和海洛因自我给药的机制，以及海洛因增强可卡因的神经化学作用。在最后一个资助期内，海洛因被证明增强了可卡因对增加伏隔核细胞外液多巴胺水平的影响，在剂量-摄入关系的上升分支上自我给药。研究还发现，这两种药物联合使用对自我给药的影响在等密度分析中是相加的，在选择过程中是协同的。此外，研究表明，腹侧苍白区和腹侧被盖区的阿片受体对自我给药的影响很重要，因为这些受体的烷基化将剂量摄入关系转变为单独的可卡因。本文拟通过实验确定内侧前额叶皮层、伏隔核、腹侧白球和腹侧被盖区谷氨酸（Glu）和v-氨基丁酸（GABA）神经元在自我给药和神经化学增强中的作用。Glu和GABA释放神经元的参与将通过微透析技术、激光捕获显微解剖、基因表达谱和离散神经元亚群的蛋白质测量来评估，以表征自我给药/海洛因组合时发生的神经适应。这些数据将用于扩展阿片类兴奋剂相互作用的模型，该模型将通过使用脑内注射特异性GABA和Glu受体激动剂和拮抗剂进一步测试，以确定和验证包含关键阿片类受体的神经元的参与，这些神经元负责对组合的自我给药和海洛因对可卡因的神经化学增强作用。相关性：自20世纪70年代以来，同时使用COC和阿片类药物组合的情况有所增加，现在已成为静脉注射药物滥用者的重要组成部分。这种共同滥用具有负面后果，因为据报道，摄入时大量使用COC会降低阿片剂成瘾者获得积极治疗结果的可能性。本申请建议继续研究可卡因和海洛因组合自我给药的机制，以及海洛因对可卡因神经化学效应的增强。显然，了解这种增强的机制可能有助于开发治疗这种共同滥用的治疗策略。

DESCRIPTION (provided by applicant): Intravenous drug use continues to be a major public health problem which is a significant vector for the spread of AIDS with the co-use of cocaine and opiate agonists increasing and recently shown to decrease the likelihood of a successful treatment outcome. This application proposes the continuation of research into the mechanisms underlying the self-administration of cocaine and heroin and the potentiation of the neurochemical effects of cocaine by heroin. During this last funding period, heroin was shown to potentiate the effects of cocaine on the increase in nucleus accumbens extracellular fluid levels of dopamine at self- administered doses on the ascending limb of the dose-intake relationship. It was also found that the effect of the combination of these two drugs on self-administration was both additive in an isobolographic analysis and synergistic in a choice procedure. In addition, it was shown that ventral pallidal and ventral tegmental area u opioid receptors are important in the effects upon self-administration since alkylation of these receptors shifted dose-intake relationships to that of cocaine alone. Experiments are proposed to define the role of glutamate (Glu) and v-aminobutyric acid (GABA) neurons in the medial prefrontal cortex, nucleus accumbens, ventral pallidum and ventral tegmental area in the effects upon self-administration and upon the neurochemical potentiation. This involvement of Glu and GABA releasing neurons will be assessed with microdialysis techniques, laser capture microdissection, gene expression profiling and protein measurements of discrete neuronal subgroups to characterize the neuro-adaptations that occur in response to the self-administration of cocaine/heroin combinations. These data will be used to expand upon a model of opiate-stimulant interactions that will be further tested through the use of intracerebral injections of specific GABA and Glu receptor agonists and antagonists to identify and verify the participation of neurons containing the critical opiate receptors responsible for the effects upon self-administration of the combination and the neurochemical potentiation of cocaine by heroin. Relevance: The concurrent use of COC and opiate combinations has increased since the 1970's and now represents a significant subset of intravenous drug abusers. This co-abuse has negative consequences since a high level of COC use at intake has been reported to decrease the likelihood of a positive treatment outcome for opiate addicts. This application proposes the continuation of research into the mechanisms underlying the self-administration of cocaine and heroin combinations and the potentiation of the neurochemical effects of cocaine by heroin demonstrated in this last funding period. Clearly, knowledge of the mechanisms of this enhancement could be helpful in the development of therapeutic strategies to treat this co-abuse.