ADENOCINE RECEPTOR POLYMORPHISMS AND PHYSIOLOGIC RESPONSE TO CAFFEINE IN PD

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。惊恐障碍（PD）是一种以反复发作和自发性惊恐发作为特征的焦虑障碍。科摩罗全国调查报告了恐慌的终生患病率和12个月患病率，其中恐慌发作为7.2%和4.2%，恐慌障碍为3.4%和2.2%（Kessler 1994）。尽管有越来越多的证据表明PD中存在不同的神经化学物质、神经肽和神经递质受体失调，但对疾病病理生理学的全面了解仍然是难以捉摸的。咖啡因是世界上使用最广泛的精神活性药物，通过拮抗腺苷受体（AR）发挥其行为效应。已经发现了四种不同的人类AR亚型，并且有证据表明咖啡因的刺激作用主要是通过抑制腺苷A2 a受体的传递引起的。在健康的不经常使用咖啡因的人中，发现咖啡因引起的焦虑与A2 a受体基因上的两个连锁多态性（1976 CT和2592 CTins多态性）之间存在显著关联。由于A2 a受体基因的1976 T/T基因型与健康对照中咖啡因诱导的焦虑增加相关，并且与惊恐障碍的易感性增加相关，我们希望研究PD中的1976 T/T基因型是否与咖啡因诱导的焦虑增加相关，以及焦虑易感性是否代表PD中的状态或特质异常。在这项初步研究中，我们将研究惊恐障碍受试者（n=10目前患病，n=10缓解）和健康对照受试者（n=10）。将测试以下假设：（1）惊恐障碍受试者在咖啡因挑战后比健康对照受试者报告更高的焦虑。(2)与具有1976 C/T和1976 C/C基因型的健康对照相比，具有1976 T/T多态性的健康对照在咖啡因刺激后将报告焦虑增加，（3）恐慌症患者与1976 C/T和1976 C/T多态性的惊恐患者相比，1976 T/T多态性的惊恐患者（目前患病且缓解）在咖啡因挑战后会报告焦虑增加。C基因型，（4）与1976 T/T基因型的健康对照相比，1976 T/T多态性的惊恐患者（两个独立的组：目前患病和缓解）在咖啡因挑战后会报告焦虑增加。所有诊断合格的受试者将进行1976 T/T多态性基因分型。如果基于基因型合格，受试者将接受为期2天的随机、双盲、平衡设计试验，口服咖啡因（480 mg）或安慰剂。这项研究将加强对腺苷受体功能在PD中的作用的理解，并首次帮助将恐慌性疾病相关效应（状态）与遗传（性状）效应分开。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Panic disorder (PD) is an anxiety disorder characterized by recurrent and spontaneous panic attacks. The lifetime and 12-month prevalence rates of panic have been reported in the National Comorbidity Survey and include 7.2% and 4.2% for panic attack, and 3.4% and 2.2% for panic disorder (Kessler 1994). A full understanding of disease pathophysiology remains elusive, although there is increasing evidence of distinct neurochemical, neuropeptide, and neurotransmitter receptor dysregulation in PD. Caffeine, the most widely used psychoactive drug in the world, exerts its behavioral effects by antagonizing adenosine receptors (AR). Four different human AR subtypes have been found and there is evidence that the stimulatory effect of caffeine is mainly caused by an inhibition of transmission via adenosine A2a receptors. A significant association has been found in healthy infrequent caffeine users between caffeine-induced anxiety and two linked polymorphisms on the A2a receptor gene, the 1976CT and 2592CTins polymorphisms. As the 1976T/T genotype of the A2a receptor gene has been associated with both increased caffeine-induced anxiety in healthy controls, and has been associated with increased vulnerability to panic disorder, we wish to study whether the 1976T/T genotype in PD is associated with increased caffeine-induced anxiety, and whether the susceptibility to anxiety represents a state or trait abnormality in PD. In this pilot study, we will study subjects with panic disorder (n=10 currently ill, n=10 remitted), and healthy controls (n=10). The following hypotheses will be tested: (1) panic disorder subjects will report higher anxiety after a caffeine challenge than the healthy control subjects. (2) healthy controls with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to healthy controls with the 1976 C/T and 1976 C/C genotypes, (3) panic patients (currently ill and remitted) with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to panic patients with the 1976 C/T and 1976 C/C genotypes, (4) panic patients (two separate groups: currently ill and remitted) with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to healthy controls with the 1976 T/T genotype. All diagnostically eligible participants will be genotyped the 1976 T/T polymorphism. If eligible based on genotype, subjects will undergo 2 days of testing in a randomized, double-blind, counter-balanced design with administration of oral caffeine (480mg) or placebo. This study will enhance understanding of the role of the adenosine receptor function in PD and, for the first time, help disentangle panic illness related effects (state) from genetic (trait) effects.