COMT Genotype and Risky Decision Making in HIV and Methamphetamine Dependence

COMT 基因型与 HIV 和甲基苯丙胺依赖的危险决策

基本信息

批准号：
7914373
负责人：
MARIANA CHERNER
金额：
$ 52.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914373
关键词：
4-aminospiroperidol AIDS/HIV problem Acute Addictive Behavior Affect Affective Age of Onset Alcohol or Other Drugs use Alleles Antisocial Personality Disorder Anxiety Area Attention Attention Deficit Disorder Attention deficit hyperactivity disorder Behavior Behavioral Brain Brain Injuries Brain region Catechol O-Methyltransferase Catechols Cognitive Collection Complex Corpus striatum structure Curiosities DOPA decarboxylase DSM-IV Data Decision Making Diagnosis Diagnostic Disinhibition Dopamine Dopamine D1 Receptor Dopamine Receptor Drug Addiction Drug abuse Emotional Environment Environmental Risk Factor Enzymes Equipment Equipment and supply inventories Esthesia Evaluation Exhibits Exploratory Behavior Exposure to Functional disorder Future Gambling Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals HIV HIV Infections HIV tat Protein Hepatitis C High Prevalence Homeostasis Human Hygiene Hyperactive behavior Impairment Impulse Control Disorders Impulsive Behavior Impulsivity Individual Individual Differences Infection Injecting drug user Injection of therapeutic agent International Intervention Interview Iowa Knowledge Lead Link Literature Maintenance Measurable Measures Mediating Mental Depression Metabolic Metabolism Methamphetamine Methamphetamine dependence Methionine Methods Methyltransferase Modeling Monitor Monoamine Oxidase Monoamine Oxidase A Moods Motor NIH Program Announcements Neurocognitive Neuropsychological Tests Neurotransmitters Outcome Participant Patient Self-Report Pattern Performance Personality Personality Traits Pharmaceutical Preparations Physiological Population Populations at Risk Prefrontal Cortex Prevalence Probability Process Psychophysiology Public Health Recruitment Activity Relative (related person)Reporting Research Research Design Rewards Risk Risk Behaviors Risk Factors Risk Reduction Risk-Taking Role Schedule Short-Term Memory Single Nucleotide Polymorphism Source Stimulus Structure Substance Addiction System Testing Thinking Tyrosine 3-Monooxygenase Unsafe Sex Utah Valine Variant Work analog base behavior measurement cognitive function computerized cost design discounting dopamine system endophenotype executive function experience extracellular flexibility frontal lobe gene environment interaction gene interaction genetic variant high risk high risk sexual behavior improved indexing insight interdisciplinary approach meetings methamphetamine exposure neurobehavioral neuropsychological novel public health relevance relating to nervous system response reuptake reward processing sound success trait transmission process

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine (METH) use is of major public health concern given its prevalence among individuals who are HIV infected and its association with HIV transmission risk behaviors, particularly high-risk sexual behavior. METH use strongly alters brain dopaminergic function. Dopamine (DA) is the primary neurotransmitter involved in the brain's reward system and is associated with impulsive behavior, hypersexuality, and many aspects of cognitive functioning, all of which contribute to decision-making choices that can impact engagement in risk behaviors. Catechol-O-methyltransferase (COMT) is the enzyme responsible for the majority of DA clearance in the frontal cortex, which, along with its connections to subcortical striatal and limbic areas, constitutes the reward-processing and decision-making substrate of the brain. A putative link has been identified between the COMT Val158Met genetic polymorphism and impaired executive functioning. Recent research also suggests a relationship between COMT Val158Met and impulsive tendencies such as novelty seeking. COMT Val alleles are confer a high rate of dopamine clearance, whereas Met alleles confer a low rate. Because both HIV and METH can damage or disrupt the frontostriatal, DA-utilizing brain areas that subserve decision-making, these conditions may interact with the COMT Val158Met genotype to exacerbate risk-taking. Therefore, we propose to investigate the effects of COMT genotype on executive functioning, preexisting impulsive traits, measurable behaviors indicating impulsivity and novelty seeking, as well as decision-making choices, on HIV risk behaviors among individuals with METH dependence and/or HIV infection. We additionally propose to investigate the role of other dopamine system genes (tyrosine hydroxylase, DOPA decarboxylase, monoamine oxidase A and dopamine receptors D1-4) that may be similarly implicated in functions leading to risky decision-making. We will also explore gene-gene interactions and gene-environment interactions (e.g., genotype interacting with amount of METH exposure) that may contribute to the prediction of propensity to engage in risk behaviors. The proposed project aims to elucidate sources of individual variability in vulnerability to DA-related dysfunction and associated risk-taking. Understanding the biologic, neurobehavioral, and personality determinants of risk-taking in the context of METH and HIV can help to explain individual differences in response to risk-reduction interventions and inform the tailoring of future interventions to improve individual success, with the goal of reducing the current rise in HIV-infection rates. PUBLIC HEALTH RELEVANCE: We will take a multidisciplinary approach to understanding the contribution of genetic, neurocognitive, psychophysiologic, and personality determinants of risky decision-making and their relationship to HIV transmission risk behaviors in the context of HIV infection and METH dependence. Findings will add to the understanding of individual differences in response to risk-reduction interventions and have the potential to inform the tailoring of future interventions.

描述（由申请人提供）：甲基苯丙胺（甲基苯丙胺（METH））的使用是主要的公共卫生问题，鉴于其在感染HIV及其与HIV传播风险行为（尤其是高风险性行为行为）相关的人中的普遍性。甲基强烈改变脑多巴胺能功能。多巴胺（DA）是参与大脑奖励系统的主要神经递质，并且与冲动行为，性交性和认知功能的许多方面有关，所有这些都有助于影响可能影响风险行为的决策选择。 Catechol-O-甲基转移酶（COMT）是负责额叶皮层中大部分DA清除率的酶，该酶及其与皮层纹状体和边缘区域的连接构成了大脑的奖励处理和决策制定底物。在COMT Val158met遗传多态性和执行功能受损之间已经确定了推定的联系。最近的研究还表明，COMT Val158met和冲动趋势（例如寻求新颖性）之间存在关系。 COMT VAL等位基因赋予多巴胺清除率很高，而遇到的等位基因赋予了低率。由于艾滋病毒和甲基苯丙胺都会损害或破坏额叶，da-利用大脑区域，以弥补决策制定，因此这些条件可能会与COMT Val158met基因型相互作用，以加剧冒险。因此，我们建议研究COMT基因型对执行功能的影响，先前存在的冲动性状，表明冲动性和新颖性的可测量行为以及决策选择，对具有METH依赖性和/或HIV感染的人的HIV风险行为。我们还建议研究其他多巴胺系统基因（酪氨酸羟化酶，DOPA脱羧酶，单胺氧化酶A和多巴胺受体D1-4）的作用，这些作用可能与导致风险决策的功能相似。我们还将探索基因基因相互作用和基因环境相互作用（例如，与甲基甲基苯甲酸甲菌群相互作用的基因型相互作用），这可能有助于预测参与风险行为的倾向。拟议的项目旨在阐明与DA相关功能障碍和相关冒险障碍的脆弱性中个人变异性的来源。了解在甲基苯丙胺和艾滋病毒背景下，在甲基苯丙胺和艾滋病毒背景下的生物学，神经行为和人格决定因素可以帮助解释响应降低风险干预措施的个体差异，并为未来的干预措施量身定制以提高个人成功，以降低当前的HIV感染率上升。公共卫生相关性：我们将采用多学科的方法来理解风险决策的遗传学，神经认知，心理生理学和人格决定因素及其与HIV感染和METH依赖性有关HIV传播风险行为的关系。调查结果将增加对降低风险干预措施的响应个人差异的理解，并有可能告知未来干预措施的裁缝。