de Beaurepaire Renaud
Groupe Hospitalier Paul-Guiraud, Villejuif, France.
Front Psychiatry. 2018 Oct 17;9:506. doi: 10.3389/fpsyt.2018.00506. eCollection 2018.
Baclofen, a GABA-B receptor agonist, is a promising treatment for alcohol use disorder (AUD). Its mechanism of action in this condition is unknown. GABA-B receptors interact with many biological systems potentially involved in AUD, including transduction pathways and neurotransmitter systems. Preclinical studies have shown that GABA-B receptors are involved in memory storage and retrieval, reward, motivation, mood and anxiety; neuroimaging studies in humans show that baclofen produces region-specific alterations in cerebral activity; GABA-B receptor activation may have neuroprotective effects; baclofen also has anti-inflammatory properties that may be of interest in the context of addiction. However, none of these biological effects fully explain the mechanism of action of baclofen in AUD. Data from clinical studies have provided a certain number of elements which may be useful for the comprehension of its mechanism of action: baclofen typically induces a state of indifference toward alcohol; the effective dose of baclofen in AUD is extremely variable from one patient to another; higher treatment doses correlate with the severity of the addiction; many of the side effects of baclofen resemble those of alcohol, raising the possibility that baclofen acts as a substitution drug; usually, however, there is no tolerance to the effects of baclofen during long-term AUD treatment. In the present article, the biological effects of baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. In conclusion, it is proposed that baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. It is also proposed that this action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems in certain regions of the brain.
巴氯芬是一种γ-氨基丁酸B（GABA-B）受体激动剂，是治疗酒精使用障碍（AUD）的一种很有前景的药物。其在这种情况下的作用机制尚不清楚。GABA-B受体与许多可能参与AUD的生物系统相互作用，包括转导途径和神经递质系统。临床前研究表明，GABA-B受体参与记忆存储和提取、奖赏、动机、情绪和焦虑；对人类的神经影像学研究表明，巴氯芬会引起大脑活动的区域特异性改变；GABA-B受体激活可能具有神经保护作用；巴氯芬还具有抗炎特性，这在成瘾背景下可能是有意义的。然而，这些生物学效应均不能完全解释巴氯芬在AUD中的作用机制。临床研究数据提供了一些可能有助于理解其作用机制的因素：巴氯芬通常会诱发对酒精的淡漠状态；巴氯芬在AUD中的有效剂量在不同患者之间差异极大；较高的治疗剂量与成瘾的严重程度相关；巴氯芬的许多副作用与酒精的副作用相似，这增加了巴氯芬作为替代药物起作用的可能性；然而，通常在长期AUD治疗期间对巴氯芬的作用不存在耐受性。在本文中，根据巴氯芬在AUD中的临床效应对其生物学效应进行了综述，假定在许多情况下，临床效应可以作为潜在生物学过程的可靠指标。总之，有人提出巴氯芬可能通过作用于多巴胺能网络的关键部分（杏仁核）来抑制线索与奖赏之间的巴甫洛夫式关联，从而使奖赏网络中的功能连接正常化。还提出巴氯芬的这种作用是由于巴氯芬和酒精在大脑的某些区域作用于相似的脑系统这一事实而成为可能的。
