Department of Psychiatry, Hôpital St Antoine, AP-HP, Paris, France ; UMR 7203, INSERM ERL 1057 - Bioactive Molecules Laboratory, Pierre and Marie Curie University, Paris, France.
Neuropsychiatr Dis Treat. 2015 Jan 17;11:165-75. doi: 10.2147/NDT.S58841. eCollection 2015.
Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.
来自神经科学多个分支的证据表明，焦虑症是由于调节情绪对潜在威胁性刺激反应的大脑回路功能障碍引起的。将焦虑症视为情绪反应调节障碍的概念是有用的，因为它可以根据异常突显的更一般模型来解释焦虑症，并且因为它确定了开发用于治疗焦虑症的心理、行为和药理学策略的途径。这些回路涉及来自杏仁核的自上而下的活动，表明存在潜在威胁性刺激，以及源自前额叶皮层的自上而下的控制机制，表明刺激的情绪突显。了解控制皮质机制的因素可能为识别更有效的认知行为策略来管理焦虑症开辟道路。杏仁核中的大脑回路被认为包含γ-氨基丁酸能（GABAergic）中间神经元的抑制性网络，因此这种神经递质在正常和病理状态下调节焦虑反应中起着关键作用。GABAA 受体上存在变构位点允许精细调节杏仁核中神经元的抑制水平，这些位点是主要类抗焦虑药物的分子靶标。这些变构位点的内源性调节剂水平的变化以及 GABAA 受体亚基组成的变化可能代表病理性焦虑状态下调神经元抑制水平的机制。神经甾体在大脑中合成并作为 GABAA 受体的变构调节剂。由于其合成本身受到应激和焦虑刺激的调节，因此靶向神经甾体-GABAA 受体轴代表了调节焦虑的有吸引力的目标。
