DBH, D2High and Cocaine Paranoia/Aversion: A [11C]PHNO PET Study

描述（由申请人提供）：在人类中，精神兴奋剂可以诱导各种厌恶的主观效应，从轻微的紧张、烦躁、易怒、冲动和怀疑到更严重的综合征后遗症，如焦虑、抑郁、愤怒、暴力和偏执。前者甚至在第一次吸毒者中或多或少地明显，后者最常见，但并非总是发生在反复、长期和高剂量吸毒中。事实上，在慢性兴奋剂暴露过程中，特别是在偏执和相关精神病症状的情况下，这些症状逐渐出现，频率和严重程度都在增加，这表明致敏机制在其病因学中发挥了作用。目前的R03申请是为了响应RFA-DA-09-016，“行为药理学和遗传学：针对个体差异”，旨在收集可卡因依赖和健康对照受试者的试验数据，探索以下因素之间潜在的药理学关系：1)多巴胺b-羟化酶（DBH）的功能遗传变异；（大脑中将多巴胺转化为去甲肾上腺素的酶），2)正电子发射断层扫描（PET）测量多巴胺D2受体（D2high）的高亲和力结合位点，以及3)个体对精神兴奋剂（哌甲酯和/或可卡因）主观厌恶作用的敏感性。这一调查途径的动机是四个独立的，尽管趋同的证据线表明一个潜在的共享的机制基础：“非常低活性”DBH多态性（TT在DBH C-1021T）的纯合性通过人类实验室方法在“体内”测量，使可卡因使用者易患妄想症。2. DBH“敲除”（DBH -/-）小鼠对兴奋剂表现出过度的敏感性，包括对通常有益剂量的可卡因的条件反射性厌恶。3. 体外（匀浆结合）和体内（微pet）数据显示，Dbh-/-小鼠纹状体d2 - high增加；在健康（非兴奋剂成瘾）人群中进行的PET研究指出，“令人不快的”哌甲酯效应与D2之间存在重要关系，D2受体水平较高，预示着厌恶脆弱性。因此，目前的R03将评估遗传因素在个体对精神兴奋剂反应中的作用，同时使用行为药理学（人类实验室）和功能脑成像（PET神经受体）方法。我们假设两组（可卡因组和健康组）中DBH C-1021T的TT纯合子会增加[11C]PHNO PET测量的D2High，反过来，这些增加将与更大的倾向于消极的兴奋剂诱导的主观效应相关。

DESCRIPTION (provided by applicant): In humans, psychostimulants can induce a variety of aversive subjective effects, ranging from mild forms of nervousness, dysphoria, irritability, impulsivity and suspiciousness to more serious syndromal sequela, such as anxiety, depression, anger, violence, and paranoia. While the former are evident to greater or lesser degrees even among first-time users, the latter most commonly, but not invariably, occur with repeated, chronic, and high-dose drug use. In fact, the progressive emergence of such symptoms with increasing frequency and severity over the course of chronic stimulant exposure, particularly in the case of paranoia and related psychotic symptoms, has suggested a role for sensitization mechanisms in their etiology [1]. The current R03 application is submitted in response to RFA-DA-09-016, "Behavioral Pharmacology and Genetics: Targeting Individual Differences," and seeks to collect pilot data in cocaine dependent and healthy control subjects exploring potential pharmacogenetic relationships between 1) functional genetic variation in dopamine b-hydroxylase (DBH; the enzyme that converts dopamine to norepinephrine in brain), 2) positron emission tomography (PET) measures of high-affinity binding sites on the dopamine D2 receptor (D2high), and 3) individual sensitivity to the subjectively aversive effects of psychostimulants (methylphenidate and/or cocaine). This avenue of investigation is motivated by four independent, albeit convergent lines of evidence suggesting a potentially shared mechanistic basis: 1. Homozygosity for a "very low activity" DBH polymorphism (TT at DBH C-1021T) predisposes cocaine users to paranoia as measured "in vivo" by human laboratory methods. 2. DBH "knock-out" (Dbh-/-) mice display an exaggerated sensitivity to stimulants, including a conditioned place aversion to normally rewarding doses of cocaine. 3. In vitro (homogenate binding) and in vivo (microPET) data demonstrate increases in striatal D2High in Dbh-/- mice, and 4. PET studies in healthy (non-stimulant addicted) humans point to important relationships between "unpleasant" methylphenidate effects and D2 - with higher receptor levels predicting aversion vulnerability. Thus, the current R03 will evaluate the role of genetic factors in the individual response to psychostimulants, using both behavioral pharmacologic (human laboratory) and functional brain imaging (PET neuroreceptor) methods. We hypothesize that TT homozygotes at DBH C-1021T in both groups (cocaine and healthy) will have increases in D2High as measured by [11C]PHNO PET and, in turn, that these increases will be associated with a greater predisposition to negative stimulant-induced subjective effects. PUBLIC HEALTH RELEVANCE: An individual's sensitivity to aversive drug effects is likely to be important not only in the manifestations and course of drug dependence (e.g., in experienced users) but also in the predisposition and/or progression to addiction (e.g., in inexperienced or drug-naive individuals). Thus, the identification of genetic and/or neurobiologic mechanisms underlying cocaine aversion may provide insights into addiction susceptibility, and in turn, improved treatment and/or prevention efforts.