Imaging Cortical Dopamine Transmission in Alcohol Dependence

描述（由申请人提供）：在过去的十年中，几个研究组已经证明酒精依赖受试者中整个纹状体和腹侧纹状体（包括边缘相关的丘脑核）水平上的刺激剂诱导的多巴胺（DA）释放减弱（Martinez et al 2005; Escherow et al 2007）。这些发现表明，在酒精依赖患者的大脑中给予兴奋剂后，DA释放的调节异常。这些研究的一个重要局限性是，D2受体和安非他明诱导的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。考虑到酒精依赖的代谢PET成像/fMRI数据表明前额叶皮层的病理激活与认知缺陷之间存在关系，这反过来又增加了药物复发的风险，因此了解DA在这一特定区域的调节作用也是非常有趣的。我们使用高D2受体亲和力PET放射性示踪剂[11 C]FLB 457测量感兴趣的皮质区域中安非他明诱导的DA释放，包括背外侧前额叶皮质（DLPFC）、内侧前额叶皮质（MPFC）、前扣带回皮质（ACC）和内侧颞叶（MTL，包括杏仁核和海马），获得了初步证据。在这个应用程序中，我们建议使用这种技术来研究安非他明诱导的DA释放的mesolimbic相关的立即奖励系统（ACC，OFC，MPFC，MTL）和中皮层相关的延迟奖励系统（DLPFC）在酗酒者和匹配的控制。基于目前的临床和临床前证据，假设与匹配的对照组相比，酒精依赖患者中安非他明诱导的多巴胺释放在中脑边缘DA系统中升高，在皮质中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传输在不同皮层区域的功能意义。了解皮质DA异常及其在成瘾性疾病（如酗酒者）中的功能意义，将有助于开发新的治疗策略。公共卫生相关性在本申请中，我们建议使用PET和fMRI来评估酗酒者大脑皮层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.