Role of Dopamine Transporter: HIV-1 Tat Protein and Nicotine Sensitization

描述（由申请人提供）：艾滋病毒阳性人群的吸烟率约为50%-70%，比非艾滋病毒人群高出2至3倍（疾病控制和预防中心，2005年）。尼古丁（NIC）是烟草中的主要增强剂，通过激活大脑中的尼古丁乙酰胆碱受体（nAChRs）来刺激中脑边缘多巴胺（DA）系统。从腹侧被盖区（VTA）到伏隔核（NAc）的DA投射在NIC介导的行为中起着关键作用，这些行为可能导致人类对NIC的渴望。与未感染艾滋病毒的人相比，艾滋病毒阳性的吸烟者更有可能产生尼古丁依赖，患上抑郁症，戒烟也更困难。综上所述，吸烟对HIV阳性个体的健康危害较高，而HIV感染可能会增加NIC依赖的风险。目前，关于hiv阳性个体对NIC依赖的脆弱性增加的神经行为机制知之甚少。HIV感染与多种因病毒蛋白存在而导致的神经损伤有关。HIV-1转录反式激活因子（Tat）蛋白是高效病毒复制所必需的，在HIV-1相关痴呆的发病机制和多巴胺能系统的协同神经毒性中起着至关重要的作用。我们最近的研究表明，纹状体内注射Tat可降低大鼠体内K+诱发的DA水平（Ferris等，2008），伏隔区内注射Tat可改变对可卡因的急性和致敏反应（Harrod等，2008）。初步结果表明，体外暴露于Tat蛋白会降低大鼠纹状体中DA转运蛋白（DAT）的功能。因此，本提案的主要实验问题是：微量注射Tat到NAc或VTA是否会产生神经变化，从而改变对急性和/或反复静脉注射（IV） NIC的敏感性？拟议的研究将验证以下假设：HIV-1 Tat蛋白改变中脑边缘多巴胺系统的功能，从而导致nic介导的行为改变。本实验主要有两个目的：1)确定微注射Tat对静脉注射NIC介导的运动致敏的影响；2)确定微注射Tat对急性或反复静脉注射NIC大鼠DAT活性和nAChRs表达的影响。本研究的长期实验目标将是阐明tat诱导的中边缘DA系统功能障碍导致NIC依赖的潜在神经生物学机制。这样的研究将为在艾滋病毒阳性人群中制定有效的戒烟计划提供新的见解。公共卫生相关性：这些结果将为HIV阳性个体对NIC依赖性增加的潜在神经行为机制提供新的见解。了解这一机制将有可能促进在艾滋病毒阳性人群中制定有效的戒烟计划。

DESCRIPTION (provided by applicant): Tobacco smoking prevalence among the HIV-positive population is approximately 50%-70%, which is 2 to 3 times higher than that in non-HIV population (Centers for Disease Control and Prevention, 2005). Nicotine (NIC), the primary reinforcing agent in tobacco, stimulates the mesolimbic dopamine (DA) system through activation of nicotinic acetylcholine receptors (nAChRs) in the brain. The DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) plays a critical role in NIC-mediated behaviors that may contribute to NIC craving in humans. Compared to non-HIV individuals, HIV-positive smokers are more likely to develop NIC dependence, suffer from depression and experience more difficulty to quit smoking. Taken together, tobacco smoking presents an elevated health hazard to HIV-positive individuals, and HIV infection may increase the risk of NIC dependence. Currently, little is known about the neurobehavioral mechanisms through which HIV-positive individuals show increased vulnerability to NIC dependence. Infection with HIV is associated with a variety of neurological impairments that result from the presence of the viral proteins. HIV-1 trans-activator of transcription (Tat) protein is essential for efficient viral replication and plays a crucial role in pathogenesis of HIV-1-associated dementia and synergistic neurotoxicity in the dopaminergic system. Our recent studies indicate that intra-striatal infusion of Tat decreases K+evoked DA levels in rats (Ferris et al., 2008) and that intra-accumbal Tat alters the acute and sensitized response to cocaine (Harrod et al., 2008). The preliminary results show that in vitro exposure to the Tat protein decreases DA transporter (DAT) function in rat striatum. Thus, the major experimental question of this proposal is: Does microinjection of Tat into either the NAc or VTA produce neural changes that alter sensitivity to acute and/or repeated intravenous (IV) NIC administration? The proposed research will test the following hypothesis: HIV-1 Tat protein alters functioning of the mesolimbic dopamine system, thereby resulting in NIC-mediated behavioral changes. The experiments proposed here are designed to focus on two specific aims: 1) To determine the effects of microinjected Tat on IV NIC-mediated locomotor sensitization, 2) To determine the effects of microinjected Tat on DAT activity and nAChRs expression in rats with acute or repeated IV NIC administration. The long-term experimental goal of the present research proposal will be to elucidate the underlying neurobiological mechanisms of Tat-induced dysfunction of mesolimbic DA system contributing to NIC dependence. Such research will provide new insights into developing effective smoking cessation programs in HIV-positive population. PUBLIC HEALTH RELEVANCE: These results will provide new insights into the underlying neurobehavioral mechanisms through which HIV- positive individuals show increased vulnerability to NIC dependence. Understanding this mechanism will have the potential to facilitate the development of effective smoking cessation programs in HIV-positive population.