Imaging Cortical Dopamine Transmission in Alcohol Dependence

描述(申请人提供)：在过去的十年里，几个小组在酒精依赖受试者的整个纹状体和腹侧纹状体(包括边缘相关的伏隔核)水平显示出兴奋剂诱导的多巴胺(DA)释放减弱(Martinez等人2005年；Volkow等人2007年)。这些发现表明，酒精依赖患者在服用兴奋剂后，大脑中DA的释放存在异常调节。这些研究的一个重要局限性是，对D2受体和苯丙胺诱导的DA释放的测量仅限于纹状体，因为所使用的配体没有提供足够的信噪比来量化纹状体外区域的D2受体。鉴于酒精依赖的代谢PET成像/fMRI数据表明前额叶皮质的病理性激活与认知障碍之间的关系，进而增加药物复发的风险，了解DA在这一特定区域的调节作用也是非常有意义的。我们获得了使用高D2受体亲和力PET放射性示踪剂[11C]FLB457来测量苯丙胺诱导的感兴趣皮质区域的DA释放的初步证据，这些区域包括背外侧前额叶(DLPFC)、内侧前额叶(MPFC)、前扣带回(ACC)和内侧颞叶(MTL，包括杏仁核和海马体)。在这一应用中，我们建议使用这项技术来研究苯丙胺在酗酒者和匹配对照组的中脑边缘相关的即刻奖赏系统(ACC，OFC，MPFC，MTL)和中皮质相关的延迟奖赏系统(DLPFC)中的DA释放。根据目前的临床和临床前证据，假设与对照组相比，酒精依赖患者苯丙胺诱导的多巴胺释放在中脑边缘DA系统中升高，在中皮质DA系统中减弱。此外，我们建议在一个简单的奖励任务中进行fMRI实验，并将其与PET结果相关联，以了解DA在不同皮质区域传递的功能意义。了解大脑皮层多巴胺的异常及其在酗酒等成瘾障碍中的功能意义将有助于推进新的治疗策略。在这一应用中，我们建议使用正电子发射计算机断层扫描(PET)和功能磁共振成像(FMRI)来评估酒精依赖者大脑皮层DA传递异常的功能意义。

DESCRIPTION (provided by applicant): Over the past decade, several groups have demonstrated a blunting in stimulant-induced dopamine (DA) release at the level of the striatum as a whole and ventral striatum (which includes the limbic-related nucleus accumbens) in alcohol dependent subjects (Martinez et al 2005; Volkow et al 2007). These findings have suggested an abnormal regulation of DA release following stimulant administration in the brain of patients with alcohol dependence. An important limitation of these studies is the fact that measurements of D2 receptors and amphetamine-induced DA release were restricted to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal regions. Given that metabolic PET imaging/fMRI data in alcohol dependence suggests a relationship between pathological activation of the prefrontal cortex and cognitive deficits, which in turn increase the risk for relapse to drugs, it is of extreme interest to understand the regulatory role of DA in this particular region as well. We obtained preliminary evidence using the high D2 receptor affinity PET radiotracer [11C]FLB 457 to measure amphetamine-induced DA release in the cortical regions of interest, including the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and medial temporal lobe (MTL, which includes the amygdala and hippocampus). In this application, we propose to use this technique to study amphetamine-induced DA release in the mesolimbic-related immediate reward system (ACC, OFC, MPFC, MTL) and mesocortical-related delayed reward system (DLPFC) in alcoholics and matched controls. Based on current clinical and preclinical evidence, the hypothesis is that amphetamine- induced dopamine release will be elevated in the mesolimbic DA system and blunted in the mesocortical DA system in patients with alcohol dependence as compared with matched controls. In addition, we propose to conduct fMRI experiments during a simple reward task and associate them with the PET findings to understand the functional significance of DA transmission in different cortical regions. The understanding of the cortical DA abnormalities and their functional significance in addictive disorders such as alcoholics will allow for the advancement of novel treatment strategies. PUBLIC HEALTH RELEVANCE In this application, we propose to use PET and fMRI to evaluate the functional significance of DA transmission abnormalities in the cortex of alcoholics.