Imaging Dopamine D2 Agonist Binding Sites in Cocaine Dependence with [11C]NPA

使用 [11C]NPA 对可卡因依赖中的多巴胺 D2 激动剂结合位点进行成像

• 批准号: 7587737
• 负责人: RAJESH NARENDRAN
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587737
• 关键词: Acute; Affinity; Agonist; Amphetamines; Animals; Annual Reports; Binding; Binding Sites; Brain; Chronic; Clinical; Clinical Investigator; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Competitive Binding; Complex; Corpus striatum structure; Coupled; Crack Cocaine; Cues; Data; Dependence; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Drug Exposure; Drug usage; Evaluation; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; GTP-Binding Proteins; Goals; Health; Human; Image; Influentials; Kinetics; Life; Ligands; Link; Literature; Measurement; Measures; Methods; Microdialysis; Nature; Neurons; Nucleus Accumbens; Patients; Peripheral; Pharmaceutical Preparations; Plague; Population; Positron-Emission Tomography; Process; Property; Public Health; Raclopride; Relapse; Relative (related person); Reporting; Reproducibility; Role; Site; Stress; Surveys; Synapses; Techniques; Testing; Ventral Striatum; addiction; cocaine exposure; cocaine use; craving; design; drug of abuse; extracellular; human subject; imaging modality; in vivo; postsynaptic; pre-clinical; preclinical study; presynaptic; psychostimulant; public health relevance; radioligand; radiotracer; receptor; response; reuptake; single photon emission computed tomography; transmission process; uptake

DESCRIPTION (provided by applicant): The sensitization response is an increased striatal dopaminergic response to a psychostimulant challenge that occurs in animals after repeated and prolonged exposure to a drug of abuse such as cocaine or amphetamine (Kalivas and Stewart, 1991; Robinson and Berridge, 1993; Vezina, 2004). This exaggerated DA response measured with microdialysis techniques is a well-validated and established phenomenon in the preclinical addiction literature. In sharp contrast to the chronic cocaine animals, three studies in cocaine dependent human subjects (CDS) have now reported a severe blunting (decrease) in the stimulant induced reduction in [11C]raclopride and [123I]IBZM in the striatum (and ventral striatum that includes the accumbens) (Malison et al., 1999; Martinez et al., 2006; Volkow et al., 1997). If one were to assume the decrease in [11C]raclopride binding following a stimulant challenge is purely reflective of presynaptic DA release, the results of the clinical imaging studies in humans suggesting a decreased dopaminergic tone (blunting) would be inconsistent with the preclinical studies in animals showing an increased dopaminergic tone (sensitization) following chronic and repeated exposure to cocaine. Nevertheless the smaller displacement of the antagonists [123I]IBZM or [11C]raclopride following stimulant challenge in CDS might result from a smaller increase in synaptic dopamine concentration following stimulants (i.e. presynaptic factors) or from decreased D2 receptor affinity for DA (i.e. postsynaptic factors), or from some combination of both factors. Available imaging methods do not allow to tease apart the respective contributions of these factors, because of the lack of radioligands to measure D2 agonist binding interactions. Despite the fact that D2 antagonist radioligands such as [123I]IBZM and [11C]raclopride have contributed tremendously to our understanding of dopamine transmission, they have been plagued by their relatively low sensitivity and ceiling effect (following stimulant challenges) which are presumably related to the fact that D2 antagonist bind to both high (D2high) and low (D2low) affinity states (Laruelle, 2000). The endogenous agonist dopamine is expected to compete efficiently with a D2 agonist radioligand such as [11C]NPA that binds preferentially to the agonist high affinity state than with an antagonist ligands such as [11C]raclopride that fails to distinguish between affinity states. Furthermore [11C]NPA is expected to have a smaller in vivo Bmax than [11C]raclopride for it binds to only a sub population of the binding of the antagonist radioligand (D2high and D2low). In this application we present evidence supporting both these hypotheses (Narendran et al., 2005; Narendran et al., 2004). This application proposes to further develop and characterize this radiotracer in healthy human subjects (test/retest reliability) and perform an exploratory study probing the role for decreased D2 agonist binding sites in cocaine dependence. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with cocaine dependence.

描述（由申请人提供）：敏化反应是对纹状体多巴胺能反应对精神刺激性挑战的增加，该反应在反复并长时间暴露于可卡因或苯丙胺等滥用药物后发生的动物（Kalivas和Stewart，Stewart，1991； Robinson和Berridge，1993; Vezina; Vezina，2004年）。通过微透析技术测量的这种夸张的DA响应是临床前成瘾文献中的验证和已建立的现象。与慢性可卡因动物形成鲜明对比的是，在可卡因依赖人类受试者（CD）中，三项研究报告了刺激性诱导的[11C] raclopide和[123i] ibzm的降低（降低）的严重钝化（降低），[123i] ibzm在纹状体（和腹侧纹状体中，包括accumbens）（包括accumbens）（包括accumbens）（包括Accumbens）（包括Malison）（Malison）（Malison）（Malison）Et。 1997）。 If one were to assume the decrease in [11C]raclopride binding following a stimulant challenge is purely reflective of presynaptic DA release, the results of the clinical imaging studies in humans suggesting a decreased dopaminergic tone (blunting) would be inconsistent with the preclinical studies in animals showing an increased dopaminergic tone (sensitization) following chronic and repeated exposure to cocaine.然而，在CD中刺激性挑战后，拮抗剂[123i] IBZM或[11C] raclopride的较小位移可能是由于兴奋剂后突触多巴胺浓度较小（即突触前因子）或降低DA的D2受体亲和力（即突触后的D2受体亲和力降低（即突触后因素）或两种因素的均等因素。由于缺乏测量D2激动剂结合相互作用的放射性配体，因此可用的成像方法不允许嘲笑这些因素的各自贡献。 Despite the fact that D2 antagonist radioligands such as [123I]IBZM and [11C]raclopride have contributed tremendously to our understanding of dopamine transmission, they have been plagued by their relatively low sensitivity and ceiling effect (following stimulant challenges) which are presumably related to the fact that D2 antagonist bind to both high (D2high) and low (D2low) affinity states (Laruelle, 2000）。预期内源性激动剂多巴胺将与D2激动剂放射线型有效竞争，例如[11C] NPA，它优先与激动剂的高亲和力结合，而不是与[11C] raclopride等拮抗剂配体（例如[11c] rapoperide）无法区分亲和力状态。此外，[11C] NPA的体内Bmax的体内BMAX比[11C] raclopride的体内较小，因为它仅与拮抗剂放射性物体的结合的亚种群结合（D2High和d2low）。在此应用中，我们提供了支持这两个假设的证据（Narendran等，2005； Narendran等，2004）。该应用建议进一步发展和表征健康人类受试者的这种放射性示意剂（测试/重新测试可靠性），并进行探索性研究，以探测可卡因依赖性降低D2激动剂结合位点的作用。公共卫生相关性：该应用程序的总体目标是开发和验证一种方法，该方法将有可能表征可卡因依赖患者的苯丙胺挑战揭示的多巴胺传播失调的突触前或后突触性质。