Brain Blood Flow Imaging of Cocaine Withdrawal&Craving

描述（由申请人提供）：可卡因使用者在遇到让人联想到可卡因的线索时，经常经历强烈的觉醒和毒品欲望。这种线索诱导的渴望状态与复发密切相关，可能反映了中脑边缘多巴胺（DA）系统活性的增加。在之前的资助期内，我们使用正电子发射断层扫描（PET，以0-15水作为灌注示踪剂）来证明可卡因的视频提示触发了寻求治疗的可卡因患者的渴望和边缘（杏仁核和前扣带）激活。我们最初的假设集中在这种线索诱导的边缘激活上（GO!）然而，从最初的资助时期开始，其他令人震惊的发现（例如，腹内侧眶额皮层的低密度和灰质低密度，VMOFC；神经心理功能障碍）表明，我们的coca在患者的额叶抑制(“停！”)电路。这些额叶区域通常调节下游的limbin区域；因此，额叶缺陷可能有助于解释我们的病人在抑制渴望和抵制药物使用方面的挣扎。

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.