Neuropathways and synaptic adaptations underlying drug addiction in central dopamine systems

对阿片类药物(海洛因)和兴奋剂(甲基苯丙胺和摇头丸)的成瘾呈上升趋势。这种上瘾的一个关键特征是反复使用这种药物的渴望加剧。被认为是调节药物渴求的一个主要大脑成分是多巴胺(DA)神经递质系统，它由中脑中的细胞组成，将神经末梢投射到参与基于奖励的学习的前脑结构。当兴奋性传入DA细胞时，DA细胞经历突触强度的长期抑制(LTD)和突触强度增强(LTP)。这些发现对药物成瘾很重要，因为苯丙胺已经被证明可以阻断LTD并增强DA细胞脑片中的LTP。因此，非法药物对LTD和LTP的改变可能是表达药物诱导的行为敏感化所必需的条件，药物诱导的行为敏感化是人类成瘾中最被接受的药物渴求模型。迄今为止，这些研究都是在脑片上进行的。因此，这种突触可塑性在中脑DA细胞中的功能重要性尚未通过活体动物前脑终末DA释放的变化来显示。我们将首次解决这个问题，通过使用一种新开发的技术记录DA细胞的激活活动和DA的释放，该技术允许在活的大脑中‘实时’(100,000样本-秒)监测DA的释放。这将使我们能够确定DA细胞中介导LTP和LTD的来源(皮质兴奋性输入)和受体机制，以及它们对DA释放的影响。通过实时测量DA释放来记录DA细胞的活动，将促进澳大利亚神经科学领域的一项新的尖端技术。这些数据将为与重复使用药物相关的DA神经元突触可塑性的功能解剖学和受体机制提供“第一”证据，并最终增强我们对人类药物成瘾神经机制的基本理解。

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.