HIV TAT protein in nicotine dependence

描述(申请人提供)：与普通人群相比，艾滋病毒感染者对尼古丁的依赖程度高得不成比例，这可能表明携带艾滋病毒的吸烟者对尼古丁和尼古丁戒断的敏感性发生了变化。改变了对 尼古丁可能是由于HIV对大脑皮质边缘结构的损伤，以及与奖赏过程，特别是多巴胺能(DA)传递密切相关的主要递质系统的失调所致。因此，迫切需要研究HIV感染者尼古丁依赖的神经生物学机制。HIV诱导的神经变性部分涉及神经毒性病毒产物，包括HIV-1 Tat，一种病毒非结构蛋白 它对病毒复制至关重要，由感染艾滋病毒的细胞分泌。已在以下位置发现TAT 大脑中的HIV-1死后脑组织。拟议的研究将在多西环素(Dox)诱导的脑靶向HIV-1 TAT转基因小鼠模型TAT诱导(ITAT)小鼠上进行。这种诱导TAT表达的小鼠模型是一种被广泛接受的艾滋病毒相关病理学的动物模型。Tat蛋白诱导小鼠中皮质边缘DA系统的神经退化和功能障碍，类似于人类艾滋病毒诱导的病理。重要的是，itat小鼠模型允许在诱导Tat表达之前将小鼠暴露于尼古丁，并在Tat表达的同时继续暴露尼古丁，以模拟艾滋病毒感染之前和期间人类吸烟的情况。有限的证据表明，TAT的表达增强了可卡因的奖赏，并导致纹状体中DA转运蛋白水平的增加，表明对药物奖赏的敏感性发生了改变。TAT表达在尼古丁奖赏和尼古丁戒断中的作用尚不清楚。尼古丁依赖的维持有几个动机来源，包括与尼古丁奖赏有关的环境或条件性线索，以及尼古丁戒断的负面后果。这项拟议的研究将在两个方面表征对ITAT小鼠的尼古丁依赖，例如尼古丁的条件性奖赏效应(特定目标1)和尼古丁戒断的情感/躯体方面(特定目标2)。神经化学研究将调查尼古丁和尼古丁戒断后皮质边缘脑区DA传递的变化(特定目标3)。据预测，itat小鼠对尼古丁的条件性奖赏效应和加剧尼古丁戒断的情感/躯体方面表现出更高的敏感度。TAT的表达也会导致DA末端的损伤，这反映在DA传递的生物标志物(DA转运体和酪氨酸羟基酶)的水平改变上。这一结果模式将支持这样的假设，即艾滋病毒感染者可能改变了DA传递，导致对尼古丁增强效应的敏感性增强，并在尼古丁戒断期间出现更明显的戒断症状，导致这一人群的高吸烟率。了解Tat表达的影响可能有助于确定开发预防性或辅助疗法来治疗艾滋病毒感染人群中的尼古丁依赖的目标。

DESCRIPTION (provided by applicant): The disproportionally higher levels of nicotine dependence among HIV-infected individuals compared to the general population may indicate altered sensitivity to nicotine and nicotine withdrawal in smokers with HIV. Altered sensitivity to nicotine may result from HIV-induced damage to corticolimbic brain structures and dysregulation of major transmitter systems critically involved in reward processes, in particular dopaminergic (DA) transmission. Thus, there is a critical need to investigate the neurobiological mechanisms underlying nicotine dependence in HIV-infected humans. HIV-induced neurodegeneration involves, in part, neurotoxic viral products including the HIV-1 TAT, a viral nonstructural protein that is critical for viral replication and is secreted by HIV-infected cells. TAT has been found in the brain of HIV-1 post-mortem brain tissue. The proposed studies will be conducted on a doxycycline (Dox)-inducible and brain targeted HIV-1 TAT transgenic mouse model, TAT- induced (iTAT) mice. This mouse model with induced TAT expression is a well-accepted animal model of HIV- related pathology. The TAT protein induces neurodegeneration and dysfunction in the mesocorticolimbic DA system in mice similar to HIV-induced pathology seen in humans. Importantly, the iTAT mouse model allows one to expose mice to nicotine before the induction of TAT expression, and continue nicotine exposure concurrently with TAT expression to mimic the human condition of smoking before and during HIV infection. Limited evidence indicates that TAT expression potentiates cocaine reward and leads to increased DA transporter levels in the striatum, suggesting altered sensitivity to drug reward. The role of TAT expression in nicotine reward and nicotine withdrawal is unknown. There are several sources of motivation that contribute to the maintenance of nicotine dependence including the environment or conditioned cues associated with nicotine reward and the negative consequences of nicotine withdrawal. The proposed studies will characterize two aspects of nicotine dependence in iTAT mice such as the conditioned rewarding effects of nicotine (Specific Aim 1) and affective/somatic aspects of nicotine withdrawal (Specific Aim 2). Neurochemical studies will investigate changes in DA transmission in corticolimbic brain areas in response to nicotine and nicotine withdrawal (Specific Aim 3). It is predicted that iTAT mice will show higher sensitivity to conditioned rewarding effects of nicotine and exacerbated affective/somatic aspects of nicotine withdrawal. TAT-expression will also result in DA terminal damage as reflected in altered levels of biomarkers of DA transmission (DA transporter and tyrosine hydroxylase). This pattern of results will support the hypothesis that HIV-infected individuals may have altered DA transmission resulting in enhanced sensitivity to the reinforcing effects of nicotine and more pronounced withdrawal symptoms during abstinence from nicotine, leading to the high smoking rates in this population. Understanding the effects of TAT expression may help identify a target for development of preventative or adjunct therapies for the treatment of nicotine dependence in the HIV-infected population.