Imaging Cortical Dopamine Transmission in Alcohol Dependence

描述（由申请人提供）：在过去的十年中，几个研究小组已经证明，在酒精依赖受试者中，兴奋剂诱导的多巴胺（DA）释放在纹状体整体和腹侧纹状体（包括边缘相关的伏隔核）水平上变钝（Martinez et al 2005; Volkow et al 2007）。这些发现提示酒精依赖患者在服用兴奋剂后，大脑中DA释放的异常调节。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。鉴于酒精依赖的代谢PET成像/fMRI数据表明前额叶皮层的病理性激活与认知缺陷之间存在关系，而认知缺陷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受体亲和性PET示踪剂[11C]FLB 457来测量安非他明诱导的DA释放在感兴趣的皮质区域，包括背外侧前额叶皮层（DLPFC）、内侧前额叶皮层（MPFC）、前扣带皮层（ACC）和内侧颞叶（MTL，包括杏仁核和海马）。在这项应用中，我们建议使用该技术研究安非他明诱导的多巴胺释放在酗酒者和匹配对照中中叶相关即时奖励系统（ACC、OFC、MPFC、MTL）和中叶皮质相关延迟奖励系统（DLPFC）中。根据目前的临床和临床前证据，我们的假设是，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，在中脑皮层DA系统中减弱。此外，我们建议在简单的奖励任务中进行fMRI实验，并将其与PET结果联系起来，以了解不同皮质区域的DA传递的功能意义。对皮质DA异常及其在成瘾障碍（如酗酒）中的功能意义的理解将促进新的治疗策略的发展。在这项应用中，我们建议使用PET和fMRI来评估酗酒者皮质中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.