Brain Blood Flow Imaging of Cocaine Withdrawal&Craving

描述（由申请人提供）：当遇到让人想起可卡因的线索时，可卡因使用者通常会经历强烈的唤醒和药物欲望。这种线索诱导的渴望状态与复发密切相关，并且可能反映了中脑边缘多巴胺（DA）系统的活性增加。在前一个资助期，我们使用正电子发射断层扫描仪（PET，0-15水作为灌注示踪剂）来证明可卡因的视频线索在寻求治疗的可卡因患者中触发了渴望和边缘系统（杏仁核和前扣带回）激活。我们最初的假设集中在这种线索诱导的边缘系统激活（GO！然而，其他引人注目的发现（例如，低活性和灰质低密度在腹内侧眶额皮质，VMOFC;神经心理功能障碍）从最初的资助期指出，缺陷，我们的古柯在患者的额叶抑制（“停止！“）电路。这些额叶区域通常调节下游的边缘区;因此，额叶的缺陷可能有助于解释我们的患者抑制渴望和抵制药物使用的斗争。 因此，我们修改了我们通常的成像范式，以捕捉大脑活动，在试图抑制线索诱导的渴望我们的药物视频。这个条件将与（作为对努力尝试的控制，渴望增加，以及我们的标准渴望诱导）形成对比。目的1是确定线索诱导的渴求的神经解剖学底物，与其尝试的抑制相反。结果将在0-15 PET（研究la）和灌注fMRI（研究ib）之间进行交叉验证。初步数据表明，尝试抑制渴望差异激活VMOFC。目的2（研究2）使用来自研究1的范例和患者来检查神经化学底物：如果中脑边缘DA增加是渴求底物，则通过GABA 1激动剂巴氯芬（20 mg q.i.d.，与安慰剂相比）应该减弱渴望和杏仁核激活。试点数据令人鼓舞。目的3（研究3）地址直接的神经化学底物，测量是否线索诱导的渴求增加，渴求抑制减少，腹侧纹状体DA释放。PET和C-11雷氯必利竞争范例用于推断内源性DA的变化。如在目标2中，巴氯芬（与安慰剂相比）预处理将用于尝试阻断线索诱导的渴望和相关的脑基质。 建议的研究解决两个“去！”和“停止！基质：它们的神经解剖学，它们的神经化学，以及它们之间的相互关系。我们有意使用与临床直接相关的操作。所揭示的底物可能与其他物质和非物质成瘾有关。

DESCRIPTION (provided by applicant): Cocaine users often experience intense arousal and drug desire when encountering cues reminiscent of cocaine. This cue-induced craving state has been closely linked to relapse, and may reflect increased activity ii the mesolimbic dopamine (DA) system. In the prior funding period, we used Positron Emission Tomograph' (PET, with 0-15 water as the perfusion tracer) to demonstrate that video cues for cocaine triggered both craving and limbic (amygdalar and anterior cingulate) activation in treatment-seeking cocaine patients. Our initial hypotheses focused on this cue-induced limbic activation (GO!") as the primary culprit in relapse vulnerability However, other striking findings (e.g., hypoacrivity and gray matter hypodensity in the ventromedial orbitofronta cortex, VMOFC; neuropsychological dysfunction) from the initial funding period point to defects in our coca in patients' frontal inhibitory ("STOP! ") circuitry. These frontal regions normally modulate downstream limbin regions; frontal defects may thus help explain our patients' struggle to inhibit craving, and to resist drug use. We have thus modified our usual imaging paradigm to capture brain activity during attempted inhibition of cue-induced craving to our drug videos. This condition will be contrasted with (as a control for effort attempted increases in craving, and with our standard craving induction. Aim 1 is to determine neuroanatomica substrates for cue-induced craving, in contrast with its attempted inhibition. Results will be cross-validate between 0-15 PET (Study la), and perfusion fMRI (Study ib). Pilot data suggest attempted craving inhibition differentially activates the VMOFC. Aim 2 (Study 2) uses the paradigm and patients from Study 1 to examination neurochemical substrates: If mesolimbic DA increase is a craving substrate, modulation of DA by the GABA 1 agonist baclofen (20 mg q.i.d., vs. placebo) should blunt craving and amygdalar activation. Pilot data an encouraging. Aim 3 (Study 3) addresses neurochemical substrates directly, measuring whether cue-induced craving increases, and craving inhibition decreases, ventral striatal DA release. PET and a C-11 raclopride competition paradigm are used to infer changes in endogenous DA. As in Aim 2, baclofen (vs. placebo) pre treatment will be used to attempt blockade of cue-induced craving and the associated brain substrate. The proposed studies address both "GO!" and "STOP!" substrates: their neuroanatomy, their neurochemistry, and their interrelation. Intentionally, we use manipulations with direct clinical relevance. The revealed substrates may well be relevant for other substance, and non-substance, addictions.