Oxytocin's novel antianxiety effect

描述(由申请者提供)：该提案推进了1)针对焦虑、抑郁、精神分裂症和自闭症等常见症状的新的心理目标--背景焦虑的经验转变，以及2)催产素，一种选择性地减少背景焦虑的激素。目前的焦虑理论强调学习，在恐惧条件作用增强，恐惧消退的损害，以及无法控制习得的恐惧导致焦虑问题。然而，过度警惕的症状和对不可预测的威胁的夸大反应通常与特定的恐惧记忆无关。因此，本提案侧重于“背景焦虑”，这是一种在威胁情况下的焦虑，其特征是对不可预测的事件感到焦虑、高度警惕和夸张的惊吓，但与习得的恐惧没有直接关系。我们最近发现，在恐惧增强的惊吓测试中，皮下注射催产素可以减少背景焦虑，而不会影响习得性恐惧。催产素是一种与社会互动、人际关系、压力和焦虑相关的激素。脑室注射催产素也可以选择性地减少背景焦虑，但剂量要高于皮下注射所需的剂量。催产素还可以减少因社交孤立而产生的夸大惊吓，这表明催产素可以提高社交弹性。该提案的具体目的是通过在几个增强的惊吓范例上测试催产素来调查背景焦虑和社交孤立焦虑的共性。将通过测试催产素激动剂和拮抗剂对背景焦虑的影响来检验催产素的药理选择性以及全身给药与中央给药的比较。将通过检测催产素对背景焦虑的长期影响来探索催产素的潜在治疗价值。最后，将通过测量与恐惧和焦虑相关的大脑回路中mRNA表达的变化来研究催产素减少背景焦虑的神经基础。该提案通过使用实验上严格的恐惧强化惊吓范例，提供了关于催产素独特的抗焦虑特征的证据，具有重要意义和创新。催产素作为一种新型背景焦虑的新型抗焦虑药物的研究将为焦虑的研究和治疗带来新的方向。 公共卫生相关性：许多焦虑症、抑郁症、精神分裂症和自闭症常见的衰弱焦虑恐惧、高度警惕和对威胁的夸大反应，但目前的抗焦虑药物通常没有帮助。对夸大惊吓的临床前研究表明，激素催产素具有特别针对这些症状的新的抗焦虑特性。对催产素减轻这些症状作用的研究将为抗焦虑治疗提供新的治疗方向。

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.