HIV TAT protein in nicotine dependence

尼古丁依赖中的 HIV TAT 蛋白

• 批准号: 8538731
• 负责人: Svetlana Semenova
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538731
• 关键词: Abstinence; Acquired Immunodeficiency Syndrome; Affective; Anhedonia; Animal Model; Anti-Retroviral Agents; Applications Grants; Area; Behavioral; Biological Markers; Brain; Brain Injuries; Cell Fractionation; Cell membrane; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Cocaine; Corpus striatum structure; Cues; DNA; Development; Doxycycline; Environment; Exhibits; Exposure to; Functional disorder; Future; General Population; HIV; HIV Infections; HIV Seropositivity; HIV-1; High Prevalence; Human; Immunohistochemistry; Individual; Injection of therapeutic agent; Knowledge; Lead; Maintenance; Measures; Methods; Morbidity - disease rate; Motivation; Mus; Nerve Degeneration; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; Prefrontal Cortex; Prevalence; Procedures; Property; Proteins; Research; Rewards; Risk; Role; Self Stimulation; Smoker; Smoking; Source; Stimulus; Structure; System; Tobacco; Tobacco smoking; Transgenic Mice; Transgenic Organisms; Travel; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Vesicle; Viral; Viral Genome; Viral Nonstructural Proteins; Withdrawal; Withdrawal Symptom; Work; brain tissue; craving; dopamine transporter; drug reward; effective therapy; improved; macrophage; mortality; mouse model; neurobiological mechanism; neurochemistry; neuropathology; neurotoxic; preference; protein expression; public health relevance; response; reward processing; transmission process

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.

描述（由申请人提供）：与一般人群相比，艾滋病毒感染者对尼古丁的依赖程度不成比例地高，这可能表明艾滋病毒吸烟者对尼古丁的敏感性和尼古丁戒断反应发生了改变。对…的敏感度改变