Department of Addiction Medicine, Central Institute for Mental Health, Mannheim, Germany.
Biol Psychiatry. 2012 Jun 1;71(11):1015-21. doi: 10.1016/j.biopsych.2011.07.034. Epub 2011 Sep 10.
In alcoholism, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome and as a key signal for dependence-related neuroplasticity. Our understanding of this pathophysiological mechanism originates largely from animal studies, but human data are needed for translation into successful medication development.
We measured brain glutamate levels during detoxification in alcohol-dependent patients (n = 47) and in healthy control subjects (n = 57) as well as in a rat model of alcoholism by state-of-the-art ¹H-magnetic magnetic resonance spectroscopy at 3 and 9.4 T, respectively.
We found significantly increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions of treatment-seeking alcoholic patients and alcohol-dependent rats versus respective control subjects. The augmented spectroscopic glutamate signal is likely related to increased glutamatergic neurotransmission because, enabled by the high field strength of the animal scanner, we detected a profoundly elevated glutamate/glutamine ratio in alcohol-dependent rats during acute withdrawal. All dependence-induced metabolic alterations normalize within a few weeks of abstinence in both humans and rats.
Our data provide first-time direct support from humans for the glutamate hypothesis of alcoholism, demonstrate the comparability of human and animal magnetic resonance spectroscopy responses, and identify the glutamate/glutamine ratio as potential biomarker for monitoring disease progression.
在酗酒中，谷氨酸能神经传递的过度活跃长期以来一直被认为与急性戒断综合征有关，并作为与依赖相关的神经可塑性的关键信号。我们对这种病理生理机制的理解主要来源于动物研究，但需要人类数据才能将其转化为成功的药物开发。
我们通过最先进的 1H 磁共振波谱技术，分别在 3 和 9.4 T 的场强下，在酒精依赖患者（n = 47）和健康对照受试者（n = 57）以及酒精依赖大鼠的模型中，在戒断期间测量大脑中的谷氨酸水平。
我们发现，在接受治疗的酒精依赖患者和酒精依赖大鼠的相应前额皮质区域中，在急性酒精戒断期间，谷氨酸水平显著升高，与各自的对照组相比。增强的光谱谷氨酸信号可能与谷氨酸能神经传递的增加有关，因为通过动物扫描仪的高强度场，我们在急性戒断期间检测到酒精依赖大鼠的谷氨酸/谷氨酰胺比值显著升高。在人类和大鼠中，所有依赖引起的代谢改变都在戒断后的几周内恢复正常。
我们的数据首次从人类中直接支持了酒精中毒的谷氨酸假说，证明了人类和动物磁共振波谱反应的可比性，并确定了谷氨酸/谷氨酰胺比值作为监测疾病进展的潜在生物标志物。
