Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner
Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner
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DOI：
10.1007/s00213-012-2702-4
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发表时间：
2012-09-01
影响因子：
3.4
通讯作者：
Slattery, David A.
中科院分区：
文献类型：
--
作者：
Toth, Iulia;Neumann, Inga D.;Slattery, David A.
催产素 (OXT) 已被提议作为创伤后应激障碍 (PTSD) 的潜在治疗剂。我们的目的是验证大脑 OXT 系统的药理学操作是否会影响提示性恐惧调节和恐惧消退。雄性大鼠和小鼠脑室内注射合成 OXT（大鼠，0.1 或 1.0 μg/5 μl；小鼠，0.1 或 1.0 μg/5 μl）。 0.5μg/2μl）和/或OXT受体拮抗剂（OXTR-A；大鼠，0.75μg/5μl）在恐惧条件反射或消退训练之前。OXT的预处理给药不影响大鼠的恐惧条件反射，但减少恐惧表达并促进恐惧消退。相比之下，OXTR-A对OXT神经传递的预适应阻断并不影响恐惧调节或恐惧表达，但会损害恐惧消退。当在消退训练之前施用时，OXT 会损害大鼠和小鼠的恐惧消退，这表明 OXT 对恐惧消退的影响在不同物种之间是保守的。这种损害是 OXTR 介导的，因为之前用 OXTR-A 治疗消除了 OXT 对恐惧消退的抑制作用。大鼠的恐惧消退受损并不是运动减少的结果，而小鼠中较高的 OXT 剂量导致恐惧表达明显减少和恐惧消退的促进是行为过度活跃的结果。这些结果表明，在创伤事件期间增加 OXT 神经传递可能会阻止厌恶记忆的形成。相比之下，在恐惧消退训练之前进行 OXT 治疗（这将是 PTSD 患者心理治疗的可比时间点），反而会延迟恐惧消退，因此，在推荐 OXT 治疗 PTSD 之前需要谨慎。
Oxytocin (OXT) has been proposed as a potential therapeutic agent for post-traumatic stress disorder (PTSD).We aimed to verify whether pharmacological manipulation of the brain OXT system affects cued fear conditioning and fear extinction.Male rats and mice were intracerebroventricularly administered synthetic OXT (rats, 0.1 or 1.0 mu g/5 mu l; mice, 0.1 or 0.5 mu g/2 mu l) and/or an OXT receptor antagonist (OXTR-A; rats, 0.75 mu g/5 mu l) either prior to fear conditioning or extinction training.Preconditioning administration of OXT did not affect fear conditioning in rats, but decreased fear expression and facilitated fear extinction. In contrast, preconditioning blockade of OXT neurotransmission by OXTR-A did not affect fear conditioning or fear expression, but impaired fear extinction. When administered before extinction training, OXT impaired fear extinction in both rats and mice, indicating that the effects of OXT on fear extinction are conserved across species. This impairment was OXTR-mediated, as the inhibitory effect of OXT on fear extinction was abolished by prior treatment with OXTR-A. The impaired fear extinction was not a result of reduced locomotion in rats, whereas an apparent decrease in fear expression and facilitation of fear extinction with the higher OXT dose in mice was the result of behavioral hyperactivity.These results suggest that increasing OXT neurotransmission during traumatic events is likely to prevent the formation of aversive memories. In contrast, OXT treatment before fear extinction training, which would be the comparable timepoint for psychotherapy in PTSD patients, rather delays fear extinction and, therefore, caution is needed before recommending OXT for the treatment of PTSD.