Neuropathways and synaptic adaptations underlying drug addiction in central dopamine systems

中枢多巴胺系统药物成瘾的神经通路和突触适应

• 批准号: nhmrc : 235307
• 负责人: Charles Blaha
• 金额: $ 12.32万
• 依托单位: Macquarie University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/neuropathways-synaptic-adaptations-dopamine-systems/77753
• 关键词: Neuropathways; synaptic; adaptations; underlying; drug

There is a rising trend in addiction to drugs, such as opioids (heroin) and stimulants (methamphetamine and ecstasy). A key feature of this addiction is intensified craving for the drug with repeated use. A major brain component thought to mediate drug-craving is the dopamine (DA) neurotransmitter system, consisting of cells in the midbrain that project nerve terminals to forebrain structures involved in reward-based learning. DA cells undergo long-term depression (LTD) and potentiation (LTP) of synaptic strength when excitatory inputs to DA cells are stimulated. These findings are important to drug addiction as amphetamine has been shown to block LTD and enhance LTP in brain slices of DA cells. Thus, changes in LTD and LTP by illicit drugs may underlie the conditions necessary for expression of drug-induced behavioural sensitisation, the best-accepted model of drug-craving in human addiction. To date, these studies have all been conducted in brain slices. Therefore, the functional importance of this synaptic plasticity in midbrain DA cells has yet to be shown in terms of changes in DA release in forebrain terminals in the living animal. For the first time we will address this issue by recording DA cell firing activity together with DA release using a newly developed technique that permits DA release to be monitored in the living brain in 'real-time' (100,000 samples-sec). This will allow us to identify the origin (cortical excitatory inputs) and receptor mechanisms that mediate LTP and LTD in DA cells and their effects on DA release. Recording DA cell activity with real-time measurement of DA release will promote a new cutting-edge technology to the Australian Neurosciences. These data will provide 'first of its kind' evidence of the functional anatomy and receptor mechanisms underlying synaptic plasticity in DA neurons associated with repeated drug use and ultimately enhance our basic understanding of the neural mechanisms of human drug addiction.

药物成瘾呈上升趋势，如类阿片（海洛因）和兴奋剂（甲基苯丙胺和摇头丸）。这种成瘾的一个关键特征是反复使用这种药物会加剧对药物的渴望。多巴胺（DA）神经递质系统被认为是介导药物渴求的一个主要大脑成分，它由中脑中的细胞组成，这些细胞将神经末梢投射到涉及奖励学习的前脑结构。当兴奋性输入被刺激到DA细胞时，DA细胞经历突触强度的长时程抑制（LTD）和增强（LTP）。这些发现对药物成瘾很重要，因为安非他明已被证明可以阻断LTD并增强DA细胞脑切片中的LTP。因此，在LTD和LTP的变化，非法药物可能是必要的条件下表达药物诱导的行为敏化，最好接受的模型，在人类成瘾的药物渴望。到目前为止，这些研究都是在大脑切片中进行的。因此，中脑DA细胞中这种突触可塑性的功能重要性尚未通过活体动物前脑末端DA释放的变化来证明。对于第一次，我们将通过记录DA细胞放电活动与DA释放一起使用一种新开发的技术，允许DA释放在活的大脑中进行监测“实时”（100，000样本秒）来解决这个问题。这将使我们能够确定起源（皮层兴奋性输入）和受体机制，介导的LTP和LTD在DA细胞和DA释放的影响。记录DA细胞活性并实时测量DA释放将为澳大利亚神经科学促进一项新的前沿技术。这些数据将提供“第一次”的证据的功能解剖学和受体机制的突触可塑性在DA神经元与重复使用药物，并最终提高我们对人类药物成瘾的神经机制的基本理解。