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

描述（由申请人提供）：HIV阳性人群的吸烟率约为50%-70%，是非HIV人群的2 - 3倍（疾病控制和预防中心，2005）。尼古丁（NIC）是烟草中的主要增强剂，通过激活大脑中的烟碱乙酰胆碱受体（nAChR）来刺激中脑边缘多巴胺（DA）系统。多巴胺从腹侧被盖区（VTA）投射到延髓核（NAc）在NIC介导的行为中起着关键作用，可能有助于人类的NIC渴求。与非艾滋病毒感染者相比，艾滋病毒阳性吸烟者更容易产生NIC依赖，患抑郁症，戒烟困难更大。总之，吸烟对艾滋病毒阳性个体的健康危害增加，艾滋病毒感染可能增加NIC依赖的风险。目前，很少有人知道的神经行为机制，通过艾滋病毒阳性个体表现出更大的脆弱性NIC依赖。HIV感染与病毒蛋白存在导致的各种神经损伤有关。HIV-1转录反式激活因子（达特）蛋白是病毒有效复制所必需的，并且在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关键作用。我们最近的研究表明，纹状体内输注达特降低了大鼠中K+诱发的DA水平（Ferris等人，2008），并且脑内达特改变了对可卡因的急性和致敏反应（Harrod等人，2008年）。初步结果表明，在体外暴露于达特蛋白降低DA转运蛋白（DAT）在大鼠纹状体的功能。因此，这个建议的主要实验问题是：微量注射达特到NAc或VTA产生神经变化，改变急性和/或重复静脉注射（IV）NIC管理的敏感性？这项拟议中的研究将验证以下假设：HIV-1达特蛋白改变中脑边缘多巴胺系统的功能，从而导致NIC介导的行为变化。本文提出的实验设计集中于两个特定的目的：1）确定显微注射达特对IV NIC介导的运动敏化的影响，2）确定显微注射达特对急性或重复IV NIC给药的大鼠中DAT活性和nAChRs表达的影响。本研究计划的长期实验目标是阐明Tat诱导的中脑边缘DA系统功能障碍导致NIC依赖的潜在神经生物学机制。这些研究将为在HIV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：这些结果将提供新的见解，通过潜在的神经行为机制，艾滋病毒阳性个体显示出增加的脆弱性，以NIC的依赖。了解这一机制将有可能促进在HIV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.