Accumbens-pallidal GABA and morphine reinforcement

描述(申请人提供)：鸦片类药物滥用仍然是一个主要问题 美国的公共卫生问题，特别是在戏剧性的 增加首次使用用户的数量。发展更有成效 药物疗法需要对神经化学物质有更详细的了解， 调节阿片类药物强化的分子和行为变量。到目前为止， 绝大多数动物研究评估阿片剂的生物学基础。 在缺乏身体依赖的情况下加强，即使身体上 依赖是人类鸦片类药物滥用的一个特征。GABA能中刺体 从NAc投射到腹侧苍白球(Vp)的神经元可能 阿片类药物增强效应的神经元基因座 阿片类药物自我给药的表现。这样做的长期目标是 建议的目的是加深对 伏隔-苍白球通路在吗啡生理给药中的作用 依赖的老鼠。第一系列研究将评估VP的相关性 GABA与吗啡依赖大鼠给药的影响。更多 具体地说，这些实验将确定细胞外的GABA 腹内侧VP和背外侧VP投射的浓度([GABA]e) 壳核和核伏隔苍白球状MSN的终端区。 这些效果将与接受带轭吗啡和 生理盐水评估VP对GABA的增强和导向作用 吗啡的药理作用。第二个系列 实验将确定VP、GABA-A和-B受体在介导 吗啡自我给药。全身性VP和腔内VP的影响 选择性拮抗剂的使用将与食物维持的使用进行比较 正在回应。第二系列实验。在第三系列实验中， 将使用区域和单细胞基因表达技术来评估 吗啡对伏核-苍白球cAMP通路转录本的调节 MSN从NAC壳到腹内侧VP和NAC核心到 背外侧副总统。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 药物的作用。

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.