Molecular mechanism of D-cycloserine action

描述(申请人提供)：仅在美国，估计就有4000万成年人患有焦虑症，这种焦虑症可能会造成令人衰弱的后果。常见形式的焦虑症包括社交焦虑、特定恐惧症和创伤后应激障碍(PTSD)。目前治疗焦虑症的方法有令人不快的副作用，可能会失败。因此，迫切需要开发新的治疗干预措施。许多焦虑症的治疗选择是基于暴露的心理治疗。在人体内的初步研究表明，D-环丝氨酸(DC)是N-甲基-D-天冬氨酸(NMDA)受体的激动剂，可以增强暴露疗法对简单和社交恐惧症、强迫症(OCD)和恐慌症的效果。尽管非常有希望的翻译结果表明，DCS在加强暴露治疗方面具有强大的作用，但其作用的分子机制尚不清楚。在这项研究中，我们将利用行为学、电生理学和生物化学技术，评估dcs对皮质-杏仁核回路突触增强或去增强的影响。这项建议的长期目标是了解NMDA受体介导的杏仁核学习机制。 公共卫生相关性：许多焦虑症的治疗选择是基于暴露的心理治疗。D-环丝氨酸(DC)增强了暴露疗法对简单和社交恐惧症、强迫症(OCD)和恐慌症的疗效。本研究将评估DCs作用的分子途径。

DESCRIPTION (provided by applicant): In the US alone, an estimated 40 million adults suffer from anxiety disorders which may have debilitating consequences. Common forms of anxiety disorders include social anxiety, specific phobias and post-traumatic stress disorders (PTSD). Current therapy for anxiety disorders have unpleasant side effects and may fail. Thus, there is an urgent need to develop new therapeutic interventions. The treatment of choice for a number of anxiety disorders is exposure-based psychotherapy. Pilot studies in human show that D-cycloserine (DCS), an agonist for N-methyl-D-aspartate (NMDA) receptors, augments the effects of exposure therapy for simple and social phobia, obsessive compulsive disorder (OCD) and panic disorder. Despite very promising translational results demonstrating a robust effect of DCS in enhancing exposure therapy, the molecular mechanism of DCS action is unknown. In this proposal using behavioral, electrophysiological and biochemical techniques we will assess the effect of DCS on synaptic strengthening or depotentiation of cortico-amygdala circuits. The long- term goal of this proposal is to understand NMDA receptor mediated mechanisms of learning in the amygdala. PUBLIC HEALTH RELEVANCE: The treatment of choice for a number of anxiety disorders is exposure-based psychotherapy. D-cycloserine (DCS) augments the effects of exposure therapy for simple and social phobia, obsessive compulsive disorder (OCD) and panic disorder. This study will assess the molecular pathway of DCS action.