Oxytocin's novel antianxiety effect

描述（由申请人提供）：该提案推进了1)对焦虑、抑郁、精神分裂症和自闭症等常见症状的新心理目标——背景焦虑的经验转变，以及2)催产素，一种选择性减少背景焦虑的激素。目前的焦虑理论强调学习，其中增强的恐惧条件反射，恐惧消退的损害，以及无法控制习得性恐惧导致焦虑问题。然而，对不可预测威胁的过度警惕和过度反应的症状通常与特定的恐惧记忆无关。因此，本研究的重点是“背景焦虑”——一种发生在威胁情境中的焦虑，其特征是焦虑忧虑、过度警惕和对不可预测事件的过度惊吓，但与习得性恐惧没有直接关系。我们最近发现皮下注射催产素，一种与社会交往、关系、压力和焦虑有关的激素，在对老鼠进行恐惧增强惊吓测试时，可以减少背景焦虑，而不影响习得性恐惧。脑室内给药催产素也有选择性地减少背景焦虑，但剂量高于皮下给药。催产素还能减少因社会孤立而产生的过度惊吓，这表明催产素能促进社会弹性。该建议的具体目的是通过测试催产素对几种增强惊吓范式的影响来研究背景焦虑和社会孤立焦虑的普遍性。通过测试催产素激动剂和拮抗剂对背景焦虑的影响，将检验催产素的药理学选择性以及全身和中枢给药的比较。催产素的潜在治疗价值将通过检查其对背景焦虑的长期影响来探索。最后，我们将通过测量与恐惧和焦虑相关的脑回路中mRNA表达的变化来研究催产素减少背景焦虑的神经基础。该建议具有重要意义和创新性，通过实验严格的恐惧增强惊吓范式提供了催产素独特的抗焦虑特征的证据。研究催产素作为新型抗焦虑剂治疗新型背景焦虑，将为焦虑研究和治疗开辟新的方向。

DESCRIPTION (provided by applicant): The proposal advances 1) an empirical shift to a new psychological target, background anxiety, for common symptoms of anxiety, depression, schizophrenia and autism disorders, and 2) oxytocin, a hormone which selectively diminishes background anxiety. Current theories of anxiety emphasize learning where enhanced fear conditioning, impairments in fear extinction, and the inability to control learned fear lead to anxiety problems. However, symptoms of hypervigilance and exaggerated responsivity to unpredictable threat are typically independent of the specific fear memories. Therefore, the present proposal focuses on "background anxiety" - a type of anxiety in threatening situations that is characterized by anxious apprehension, hypervigilance and exaggerated startle to unpredictable events, but is not directly related to learned fear. We have recently found that subcutaneously administered oxytocin, a hormone that is associated with social interaction, affiliation, stress and anxiety, reduces background anxiety without affecting learned fear in a fear-potentiated startle test in rats. Intracerebroventricular administration of oxytocin also selectively reduces background anxiety, but with a higher dose than is needed with subcutaneous delivery. Oxytocin also reduces exaggerated startle produced by social isolation demonstrating that oxytocin promotes social resiliency. The specific aims of the proposal are to investigate the generality of background anxiety and social isolation anxiety by testing oxytocin on several potentiated startle paradigms. The pharmacological selectivity of oxytocin and comparison of systemic vs. central administration will be examined by testing oxytocin agonists and antagonists on background anxiety. The potential therapeutic value of oxytocin administration will be explored by examining its long-term effects on background anxiety. Finally, the neural basis of oxytocin's reduction of background anxiety will be studied by measuring changes in mRNA expression in brain circuits related to fear and anxiety. The proposal has significance and innovation by providing evidence about oxytocin's unique antianxiety profile using experimentally rigorous fear-potentiated startle paradigms. The investigation of oxytocin as a novel antianxiety agent for a novel type of background anxiety should lead to new directions for anxiety research and therapeutics. PUBLIC HEALTH RELEVANCE: Debilitating anxious apprehension, hypervigilance, and exaggerated responsivity to threat are common to many anxiety disorders, depression, schizophrenia and autism, but are typically not helped by current antianxiety medications. Preclinical studies of exaggerated startle suggest that the hormone oxytocin has novel anti-anxiety properties specifically for these symptoms. The research on oxytocin's effects of reducing these symptoms should provide new therapeutic directions for antianxiety treatments.