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（由申请人提供）：在人类中，精神刺激物可以诱导多种厌恶的主观效应，范围从轻度的神经质，烦躁不安，烦躁，冲动和可疑性到更严重的综合综合症，例如焦虑，抑郁，抑郁，愤怒，暴力和paranoia。尽管前者甚至在首次使用者中甚至在更大的程度上都显而易见，但后者最常见但并非总是会发生，而重复，慢性和高剂量吸毒。实际上，在慢性刺激性暴露过程中，这种症状的逐渐出现，频率和严重程度的增加，尤其是在偏执狂和相关的精神病症状的情况下，已经提出了致敏机制在病因中的作用[1]。当前的R03应用是根据RFA-DA-09-016提交的，“行为药理学和遗传学：靶向个体差异”，并试图收集可卡因依赖性和健康的对照受试者中的试验数据，以探索1）在多巴胺B-Hydroxyse中的功能遗传学之间的潜在药物遗传学关系（DB-Hydroxys depbhase n d.dbhase n d.dbhres n d.dbh seme n d.dbh;在大脑中），2）在多巴胺D2受体（D2High）上的高亲和力结合位点的正电子发射断层扫描（PET），以及3）对心理刺激剂（甲基苯甲酯和/或可卡因）主观厌恶效应的个体敏感性。这种调查途径是由四个独立的，尽管有收敛的证据来激励的，但表明了潜在共同的机理基础：1。“非常低的活动” DBH多态性（DBH C-1021T的TT）易孕症，使可卡因对帕拉诺亚的可卡因对帕拉诺亚的使用，如人类实验室方法所测量的“ In Vivo”。 2。DBH“敲除”（DBH - / - ）小鼠对兴奋剂的敏感性夸张，包括条件的位置对通常奖励可卡因的敏感性。 3。体外（匀浆结合）和体内（MICROPET）数据表明，DBH - / - 小鼠的纹状体D2高以及4。对健康（非刺激性上瘾）Human的PET研究指向“不愉快的”甲基化偶然效应和d2-具有较高受体水平的“不愉快”的重要关系。因此，当前的R03将使用行为药理（人类实验室）和功能性脑成像（PET神经受感受器）方法来评估遗传因素在对心理刺激剂的个人反应中的作用。我们假设这两组中DBH C-1021T的TT纯合子（可卡因和健康）将增加D2High的增加，这是通过[11C] Phno PET测量的，而这些增加将与这些增加有关，这些增加将与对负面刺激性诱导的主观效应的倾向更大。 公共卫生相关性：个人对厌恶药物作用的敏感性不仅在药物依赖的表现和过程中（例如，在经验丰富的用户中）也很重要，而且在倾向和/或成瘾的倾向和/或进展中（例如，经验不足或毒品或药物不足的个体）。因此，鉴定可卡因厌恶基础的遗传和/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。

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