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

描述（由申请人提供）：在人体中，精神兴奋剂可诱导各种令人厌恶的主观效应，范围从轻度形式的神经紧张、烦躁不安、易怒、冲动和多疑到更严重的综合征后遗症，如焦虑、抑郁、愤怒、暴力和偏执。虽然前者甚至在首次使用者中也或多或少地明显，但后者最常见，但并非总是发生在重复，慢性和高剂量药物使用中。事实上，在慢性兴奋剂暴露过程中，这些症状的逐渐出现频率和严重程度增加，特别是在偏执狂和相关精神病症状的情况下，表明致敏机制在其病因学中的作用[1]。当前的R 03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”而提交的，旨在收集可卡因依赖和健康对照受试者的初步数据，探索1）多巴胺b-羟化酶的功能性遗传变异之间的潜在药物遗传学关系（胸径;在脑中将多巴胺转化为去甲肾上腺素的酶），2）多巴胺D2受体（D2 high）上的高亲和力结合位点的正电子发射断层扫描（PET）测量，和3）个体对精神兴奋剂（哌醋甲酯和/或可卡因）的主观厌恶效应的敏感性。这条调查途径的动机是四个独立的，虽然收敛线的证据表明一个潜在的共享机制的基础：1。纯合性的“非常低的活动”DBH多态性（TT在DBH C-1021 T）易患妄想症的可卡因用户测量“体内”的人类实验室方法。2. DBH“敲除”（Dbh-/-）小鼠对兴奋剂表现出过度的敏感性，包括对通常奖励剂量的可卡因的条件性位置厌恶。3.体外（匀浆结合）和体内（microPET）数据表明Dbh-/-小鼠纹状体D2 High增加，4.在健康（非兴奋剂成瘾）人群中进行的PET研究指出了“令人不快的”哌甲酯效应与D2之间的重要关系-较高的受体水平预示着厌恶脆弱性。因此，目前的R 03将使用行为药理学（人类实验室）和功能性脑成像（PET神经受体）方法评估遗传因素在个体对精神兴奋剂反应中的作用。我们假设两组（可卡因组和健康组）中DBH C-1021 T处的TT纯合子通过[11 C]PHNO PET测量的D2 High会增加，反过来，这些增加将与更大的倾向于负面刺激诱导的主观效应相关。 公共卫生相关性：一个人对厌恶药物作用的敏感性可能不仅在药物依赖的表现和过程中很重要（例如，在有经验的使用者中）而且在成瘾倾向和/或进展中（例如，在没有经验的或未使用过药物的个体中）。因此，可卡因厌恶的遗传和/或神经生物学机制的识别可能会提供成瘾易感性的见解，反过来，改善治疗和/或预防工作。

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.