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

DBH、D2High 和可卡因偏执/厌恶：[11C]PHNO PET 研究

• 批准号: 7762102
• 负责人: ROBERT T MALISON
• 金额: $ 20.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762102
• 关键词: Affinity; Agonist; Anger; Anxiety; Behavioral; Binding; Binding Sites; Bolus Infusion; Brain; Brain imaging; Chronic; Cocaine; Cocaine Users; Corpus striatum structure; Data; Dopamine; Dopamine D2 Receptor; Dose; Drug Addiction; Drug usage; Enzymes; Equilibrium; Ethics; Etiology; Frequencies; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Health; Homozygote; Human; Image; Impulsivity; In Vitro; Individual; Individual Differences; Infusion procedures; Investigation; Knock-out; Laboratories; Measures; Methods; Methylphenidate; Mixed Function Oxygenases; Mus; Nervousness; Norepinephrine; Paranoia; Pharmaceutical Preparations; Pharmacogenetics; Population; Positron-Emission Tomography; Predisposition; Prevalence; Prevention; Reporting; Rewards; Role; Self Administration; Sensory Receptors; Severities; Symptoms; Time; Tracer; Variant; Violence; addiction; base; behavioral pharmacology; cocaine use; depression; dysphoria; experience; improved; in vivo; insight; psychostimulant; public health relevance; receptor; response; stimulant addict; trait

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.

描述（由申请人提供）：在人类中，精神兴奋剂可引起多种令人厌恶的主观效应，从轻微的紧张、烦躁、烦躁、冲动和多疑到更严重的综合症后遗症，如焦虑、抑郁、愤怒、暴力和偏执。虽然前者即使在初次吸毒者中也或多或少地明显，但后者最常见（但并非总是）在重复、长期和高剂量吸毒时发生。事实上，在长期接触兴奋剂的过程中，随着频率和严重程度的增加，此类症状逐渐出现，特别是在偏执和相关精神病症状的情况下，表明敏化机制在其病因学中发挥着作用[1]。当前的 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”而提交的，旨在收集可卡因依赖者和健康对照受试者的试点数据，探索 1) 多巴胺 b-羟化酶（DBH；将多巴胺转化为去甲肾上腺素的酶）的功能遗传变异之间潜在的药物遗传学关系 大脑中），2）正电子发射断层扫描（PET）测量多巴胺 D2 受体（D2high）上的高亲和力结合位点，以及 3）个人对精神兴奋剂（哌醋甲酯和/或可卡因）主观厌恶作用的敏感性。这一研究途径的动机是四个独立但趋同的证据线索，表明可能存在共同的机制基础：1.“活性极低”的 DBH 多态性（TT at DBH C-1021T）的纯合性使可卡因使用者易患偏执狂（通过人类实验室方法“体内”测量）。 2. DBH“敲除”（Dbh-/-）小鼠对兴奋剂表现出过度的敏感性，包括对正常剂量的可卡因产生条件性厌恶。 3. 体外（匀浆结合）和体内（microPET）数据表明 Dbh-/- 小鼠纹状体 D2High 有所增加，4. 对健康（非兴奋剂成瘾）人类的 PET 研究指出“令人不愉快的”哌醋甲酯效应与 D2 之间存在重要关系 - 较高的受体水平预示着厌恶脆弱性。因此，当前的 R03 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）方法来评估遗传因素在个体对精神兴奋剂的反应中的作用。我们假设两组（可卡因组和健康组）中 DBH C-1021T 的 TT 纯合子通过 [11C]PHNO PET 测量，D2High 都会增加，反过来，这些增加将与更容易受到负面兴奋剂引起的主观影响相关。 公共卫生相关性：个体对药物厌恶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），而且在成瘾的倾向和/或进展方面（例如，在缺乏经验或未接触过药物的个体中）也很重要。因此，识别可卡因厌恶背后的遗传和/或神经生物学机制可以提供对成瘾易感性的见解，进而改善治疗和/或预防工作。