PET STUDIES IN ALCOHOLISM: MEASUREMENT OF BRAIN METABOLISM BRAIN DOPAMINE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。酒精诱导自我管理和依赖的神经化学机制还知之甚少。使用正电子发射计算机断层扫描，我们发现酗酒者的大脑GABA活性降低。虽然GABA功能下降可以解释酒精作为一种增加抑制性神经传递的方式，但它本身并不能解释成瘾行为。我们假设，酗酒者失控和强制饮酒是继发性的，因为GABA对多巴胺系统的调节减少，导致受DA调节的脑区功能异常，并对增加DA的刺激反应增强。这使得酒精更加强健，但它也增强了应激刺激的厌恶品质。我们还假设，DA活动异常导致眼眶额区功能障碍，这是导致失控和强迫饮酒的机制之一。在酗酒的受试者中，我们已经记录了DA D2受体的减少，该受体主要位于GABA细胞，然而还没有研究来测量酗酒者的DA细胞的功能。我们用正电子发射计算机断层扫描和[11C]拉克洛必利测量DA在大脑中的释放，它提供了DA细胞功能的间接测量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Neuro-chemical mechanisms by which ethanol induces self-administration and dependence are poorly understood. Using PET we have documented decreased brain GABA activity in alcoholics. While decreased GABA function could explain the use of alcohol as a way of increasing inhibitory neurotransmission it does not explain the addictive behavior per se. We hypothesize that the loss of control and the compulsive administration of alcohol in the alcoholic is secondary to decreased GABA modulation of the dopamine system, which results in abnormal function of brain regions modulated by DA and in accentuated responses to stimuli that increase DA. This makes alcohol more reinforcing but it also enhances the aversive quality of stressful stimuli. We also hypothesize that abnormal DA activity leads to dysfunction of orbit frontal regions, which we postulate is one of the mechanisms leading to the loss of control and the drive to compulsively administer alcohol. In alcoholic subjects we have documented reductions in DA D2 receptors, which are mostly located in the GABA cells, however no studies have been done to measure the function of the DA cells in alcoholics. DA release in brain, which we measure with PET and [11C] raclopride, provides an indirect measure of the function of the DA cells.