Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80 - 82/III, A-6020 Innsbruck, Austria.
Neuropharmacology. 2013 Jan;64(4):414-23. doi: 10.1016/j.neuropharm.2012.06.001. Epub 2012 Jun 18.
Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
焦虑症的特征是持续的、过度的恐惧。能够逆转恐惧消退缺陷的治疗干预方法代表了一种可行的治疗这些疾病的方法。我们之前报道过，129S1/SvImJ（S1）小鼠在正常恐惧条件反射后没有表现出消退学习。我们现在证明，在 S1 小鼠的密集消退训练中，弱恐惧条件反射确实允许恐惧减少，但显示出消退记忆巩固/检索的特定缺陷。用 d-环丝氨酸（N-甲基-d-天冬氨酸部分激动剂）或 MS-275（组蛋白去乙酰化酶（HDAC）抑制剂）在消退训练后应用，可挽救这种受损的消退巩固/检索。接下来，我们检查了不同药物和非药物操作的能力，以挽救正常恐惧条件反射后 S1 中的极端恐惧消退缺陷，最终目的是在消退检索测试中产生低恐惧水平。结果表明，在消退训练期间对伏隔核（腹侧纹状体）施加高频刺激的深部脑刺激（DBS）确实显著降低了消退检索时的恐惧程度，与假刺激对照相比。用丙戊酸（GABA 能增强剂和 HDAC 抑制剂）或 AMN082[代谢型谷氨酸受体 7（mGlu7）激动剂]预先进行消退训练给药，可挽救获得性消退和消退巩固/检索缺陷，而 MS-275 或 PEPA（AMPA 受体增强剂）未能影响 S1 小鼠的消退获得。总的来说，这些数据确定了 DBS 和各种药物治疗的潜在有益效果，包括具有 HDAC 抑制或 mGlu7 激动特性的药物治疗，作为克服基于暴露的治疗中治疗抵抗的辅助手段。本文是题为“认知增强剂”的特刊的一部分。
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