COMT Genotype and Risky Decision Making in HIV and Methamphetamine Dependence

说明（由申请人提供）：甲基苯丙胺（冰毒）的使用是一个重大的公共卫生问题，因为它在艾滋病毒感染者中流行，并与艾滋病毒传播风险行为，特别是高风险的性行为有关。使用冰毒会强烈改变大脑多巴胺能功能。多巴胺（DA）是参与大脑奖励系统的主要神经递质，与冲动行为、性欲亢进和认知功能的许多方面有关，所有这些都有助于影响风险行为参与的决策选择。儿茶酚- o -甲基转移酶（COMT）是负责额叶皮层大部分DA清除的酶，它与皮层下纹状体和边缘区域的连接，构成了大脑的奖励处理和决策基础。COMT Val158Met基因多态性与执行功能受损之间存在假定的联系。最近的研究还表明，COMT Val158Met与追求新奇等冲动倾向之间存在关系。COMT Val等位基因具有较高的多巴胺清除率，而Met等位基因具有较低的清除率。因为HIV和冰毒都可以破坏或破坏额纹状体，利用da的大脑区域，这些条件可能与COMT Val158Met基因型相互作用，从而加剧冒险行为。因此，我们建议研究COMT基因型对甲基安非他明依赖和/或HIV感染个体的执行功能、先前存在的冲动特征、表明冲动和追求新奇的可测量行为以及决策选择的影响。我们还建议研究其他多巴胺系统基因（酪氨酸羟化酶、多巴脱羧酶、单胺氧化酶A和多巴胺受体D1-4）的作用，这些基因可能同样涉及导致风险决策的功能。我们还将探讨基因-基因相互作用和基因-环境相互作用（例如，基因型与甲基安非他明暴露量的相互作用），这可能有助于预测从事危险行为的倾向。拟议的项目旨在阐明个体易受da相关功能障碍和相关风险的差异的来源。了解甲基安非他明和艾滋病毒背景下冒险行为的生物学、神经行为和人格决定因素，有助于解释个体对降低风险干预措施的反应差异，并为未来干预措施的量身定制提供信息，以提高个体成功率，目标是降低当前艾滋病毒感染率的上升。公共卫生相关性：我们将采取多学科的方法来了解遗传、神经认知、心理生理和人格因素对风险决策的影响，以及它们与艾滋病毒感染和冰毒依赖背景下艾滋病毒传播风险行为的关系。研究结果将有助于了解个体对降低风险干预措施的反应差异，并有可能为未来干预措施的量身定制提供信息。

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.