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

描述(申请人提供)：致敏反应是在反复和长期接触滥用药物，如可卡因或安非他明后，动物对精神刺激剂挑战的纹状体多巴胺能反应增加(Kalivas和Stewart，1991；Robinson和Berbridge，1993；Vezina，2004)。用微透析技术测量的这种夸张的DA反应在临床前成瘾文献中是一个得到充分验证和确立的现象。与慢性可卡因依赖动物形成鲜明对比的是，三项关于可卡因依赖人类受试者(CDS)的研究现在报告了刺激剂诱导的纹状体(以及包括伏隔核的腹侧纹状体)中[11C]raclopide和[123I]IBZM的严重钝化(减少)(Malison等人，1999年；Martinez等人，2006年；Volkow等人，1997年)。如果人们假设兴奋剂激发后[11C]雷氯必利结合的减少纯粹是突触前DA释放的反映，那么人类临床成像研究的结果表明，多巴胺能张力(钝化)的降低与动物的临床前研究表明，在长期和重复暴露可卡因后，多巴胺能张力(敏化)增加是不一致的。然而，在刺激CDS后，[123I]IBZM或[11C]raclopide拮抗剂的位移较小，可能是由于刺激剂引起的突触多巴胺浓度的较小增加(即突触前因子)，或者是由于D2受体对DA的亲和力降低(即突触后因子)，或者是两种因素的某种组合。现有的成像方法不允许梳理这些因素的各自贡献，因为缺乏放射性配体来测量D2激动剂的结合作用。尽管D2拮抗剂放射性配基如[123I]IBZM和[11C]雷氯普利为我们理解多巴胺的传递做出了巨大贡献，但它们仍然受到相对较低的敏感性和天花板效应的困扰(在兴奋剂挑战之后)，这可能与D2拮抗剂与高(D2High)和低(D2low)亲和力状态结合的事实有关(Laruelle，2000)。内源性激动剂多巴胺有望与D2激动剂放射性配体(如[11C]NPA)有效竞争，后者优先与激动剂高亲和力状态结合，而不是与未能区分亲和力状态的拮抗剂配体(如[11C]雷氯普利)竞争。此外，预计[11C]NPA在体内的Bmax比[11C]雷氯普利小，因为它只与拮抗剂放射性配体结合的一个亚群(D2high和D2low)结合。在本申请中，我们提出了支持这两种假说的证据(Narendran等人，2005年；Narendran等人，2004年)。本申请建议在健康受试者中进一步开发和表征这种放射性示踪剂(测试/重新测试可靠性)，并进行一项探索性研究，探讨D2激动剂结合位点减少在可卡因依赖中的作用。与公共健康相关：这项应用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递异常的突触前或突触后性质。

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.