Accumbens-pallidal GABA and morphine reinforcement

描述（由申请人提供）：阿片类药物滥用仍然是一个主要的 美国的公共卫生问题，特别是鉴于戏剧性的 第一次使用者的数量增加。开发更有效的 药物治疗需要更详细地了解神经化学物质， 分子和行为变量介导的阿片强化。到目前为止， 绝大多数动物研究评估了鸦片制剂的生物学基础， 在没有身体依赖的情况下，即使身体依赖， 依赖性是人类滥用阿片剂的一个特征。GABA能中等多刺 从NAc投射到腹侧苍白球（VP）的神经元可能是 神经元位点的阿片类药物的强化作用，是必要的 阿片类药物自我给药的表达。长期目标是 建议是进一步了解参与的情况， 吗啡自身给药的丘脑-苍白球通路 依赖的老鼠第一系列的研究将评估VP GABA对吗啡依赖大鼠的影响。更 具体地说，这些实验将确定细胞外GABA VP腹内侧和背外侧投射中的[GABA]e浓度 分别是壳和核心丘脑-苍白球MSN的末端区域。 这些效果将与接受吗啡轭的受试者进行比较， 生理盐水，以评估VP GABA在增强和直接 吗啡的药理作用。第二系列 实验将确定VP GABA-A和-B受体在介导 吗啡自我给药全身和静脉注射VP的影响 将选择性拮抗剂的给药与食物维持的给药进行比较。 响应.第二个系列的实验。在第三系列实验中， 区域和单细胞基因表达技术将用于评估 吗啡诱导的丘脑-苍白球cAMP通路转录调控 从NAc壳到腹内侧VP和NAc核心到 背外侧副静脉多个基因表达水平的变化将是 根据吗啡强化和直接药理作用进行评估 的药物。

DESCRIPTION (provided by applicant): Opiate abuse continues to be a major public health concern in the United States, especially in light of the dramatic increase in the number of first time users. The development of more effective pharmacotherapies requires a more detailed understanding of the neurochemical, molecular and behavioral variables that mediate opiate reinforcement. To date, a vast majority of animal studies assess the biological underpinnings of opiate reinforcement in the absence physical dependence, even though physical dependence is a characteristic of human opiate abuse. GABAergic medium spiny neurons projecting from the NAc to the ventral pallidum (VP) are likely neuronal loci for the reinforcing effects of opiates and are necessary for the expression of opiate self-administration. The long-term objective of this proposal is to further the understanding of the involvement of the accumbens-pallidal pathway in morphine self-administration in physically dependent rats. The first series of studies will assess the correlation of VP GABA with the effects of morphine administration in dependent rats. More specifically, these experiments will determine extracellular GABA concentrations ([GABA]e) in the ventromedial VP and dorsolateral VP, projection terminal regions of the shell and core accumbal-pallidal MSNs, respectively. These effects will be compared with subjects receiving yoked morphine and saline to assess the contribution of VP GABA in the reinforcing and direct pharmacological effects of morphine respectively. The second series of experiments will determine the role of VP GABA-A and -B receptors in mediating morphine self-administration. The effects of systemic and intra-VP administration of selective antagonists will be compared with food-maintained responding. A second series of experiments. In a third series of experiments, regional and single cell gene expression techniques will be employed to assess morphine-induced regulation of cAMP pathway transcripts in accumbens-pallidal MSN projections from the NAc shell to the ventromedial VP and NAc core to the dorsolateral VP. Changes in the expression levels of multiple genes will be assessed in terms of morphine reinforcement and direct pharmacological effects of the drug.