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: 7924140
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924140
• 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; Mental Depression; 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; 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(申请人提供)：在人类中，精神刺激剂可以引起各种令人厌恶的主观效果，从轻微的紧张、烦躁、易怒、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。即使在首次吸毒者中，前者或多或少也很明显，而后者最常见，但不是一成不变的，发生在反复、长期和高剂量药物使用中。事实上，在慢性兴奋剂暴露的过程中，这种症状逐渐出现，频率和严重程度越来越高，特别是在偏执狂和相关的精神症状的情况下，这表明致敏机制在其病因中发挥了作用[1]。目前的R03申请是根据RFA-DA-09-016，“行为药理学和遗传学：针对个体差异”提交的，旨在收集可卡因依赖和健康对照受试者的试点数据，探索1)多巴胺b-羟基酶(DBH；大脑中将多巴胺转化为去甲肾上腺素的酶)的功能遗传变异，2)正电子发射断层扫描(PET)测量多巴胺D2受体(D2High)上高亲和力结合位点的方法，以及3)个体对精神刺激剂(哌甲酯和/或可卡因)主观厌恶效应的敏感性。这一调查途径是由四条独立的、尽管是趋同的证据所推动的，这些证据表明了一个潜在的共同的机制基础：1.根据人类实验室方法的测量，“非常低活性”的DBH多态(位于DBH C-1021T的TT)的纯合子使可卡因使用者倾向于偏执。2.DBH“敲除”(DBH-/-)小鼠对刺激物表现出夸大的敏感性，包括对正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D2High增加；4.在健康(非兴奋剂成瘾)人中进行的PET研究指出，“令人不快的”哌甲酯效应和D2-之间存在重要关系，较高的受体水平预示着厌恶易感性。因此，目前的R03将使用行为药理学(人体实验室)和脑功能成像(PET神经感受器)方法来评估遗传因素在个体对精神刺激剂反应中的作用。我们假设两组(可卡因和健康人)在DBH C-1021T处的TT纯合子将会有[11C]PHNO PET测量的D2High的增加，反过来，这些增加将与更容易受到负面刺激诱导的主观影响有关。 公共卫生相关性：个人对不良药物效应的敏感性可能不仅在药物依赖的表现和过程中(例如，在有经验的吸毒者中)，而且在成瘾的易感性和/或发展过程中(例如，在缺乏经验或药物幼稚的个人中)。因此，识别可卡因厌恶的遗传和/或神经生物机制可能有助于深入了解成瘾易感性，进而改进治疗和/或预防工作。

项目成果

Relationships between dopamine D2/3 receptor availability and social-environmental factors in humans.

• DOI: 10.1016/j.neulet.2022.136463
• 发表时间: 2022-02-06
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Calakos KC;Rusowicz A;Pittman B;Gallezot JD;Potenza MN;Cosgrove KP;Matuskey D
• 通讯作者: Matuskey D