School of Psychology, The University of New South Wales, Sydney 2052, Australia.
Learn Mem. 2012 Sep 14;19(10):461-9. doi: 10.1101/lm.026674.112.
The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.
NMDA 受体部分激动剂 D-环丝氨酸（DCS）增强了大鼠习得性恐惧的消退和焦虑障碍患者的暴露疗法。尽管有这些益处，但对于 DCS 促进恐惧丧失的机制知之甚少。本研究考察了 DCS 是否通过以下两种方式增强了消退的保持：（1）减少条件刺激（CS）处理，或（2）促进对环境线索的条件抑制的发展。在消退前给予 DCS 的大鼠表现出增强的长期消退保持（实验 3 和 4）。在条件作用之前作为预暴露呈现的相同的非强化 CS 程序在测试时也减少了冻结，证明了潜伏抑制（实验 1）。在产生弱（实验 2）或强（实验 3）潜伏抑制表达的参数下，在预暴露之前给予 DCS 对潜伏抑制没有影响。因此，DCS 促进了涉及 CS 单独暴露的学习，但仅当这些暴露发生在（消退）之后而不是（潜伏抑制）之前。我们还使用了延迟测试程序来检查在消退前给予 DCS 的大鼠，消退环境是否获得了对大鼠的抑制特性。使用三种不同的足底电击强度，没有证据表明 DCS 促进了对消退环境的关联抑制的积累（实验 4）。本研究结果表明，DCS 并没有通过减少 CS 处理或使消退环境成为条件抑制剂来促进消退。对 DCS 增强消退的机制的研究对于理解如何抑制恐惧是有价值的。
