Department of Psychological Sciences, Kent State University, Kent, OH, 44242, USA.
Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA.
Psychopharmacology (Berl). 2021 Aug;238(8):2059-2071. doi: 10.1007/s00213-021-05831-w. Epub 2021 Apr 14.
Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABA receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABA receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABA receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABA receptors, we blocked presynaptic GABA receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABA receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABA receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.
焦虑和创伤相关障碍在全球范围内非常普遍，并且与关联的恐惧学习改变有关。尽管暴露疗法有效，旨在减少关联的恐惧反应，但复发率仍然很高。这部分是由于暴露疗法的上下文特异性，它是一种灭绝。许多研究表明，当老鼠在灭绝的环境之外进行测试时，恐惧会复发，这被称为恐惧更新。使用巴甫洛夫式恐惧条件反射和灭绝，我们可以研究灭绝和更新的机制。目前实验的目的是确定突触前 GABA 受体在这两个过程中的作用。我们实验室之前的工作表明，遗传删除或药理学抑制谷氨酸能末梢的突触前 GABA 受体抑制可降低上下文特异性并导致泛化。因此，我们假设失活这些突触前 GABA 受体可以用来减少与恐惧灭绝训练相关的上下文特异性，并在老鼠在灭绝环境之外进行测试时抑制更新。使用 CGP 36216，一种针对突触前 GABA 受体的拮抗剂，我们在雄性和雌性老鼠的灭绝学习的各个时间点通过脑室注射阻断突触前 GABA 受体。结果表明，阻断这些受体的前和后灭绝训练仅导致雄性老鼠的灭绝学习增强。我们还发现，当雄性老鼠在灭绝环境之外进行测试时，灭绝后 CGP 的输注会降低更新率。为了尝试在灭绝电路的区域内定位突触前 GABA 受体的功能，我们将 CGP 局部注入基底外侧杏仁核或背海马。当 CGP 直接注入这些区域时，我们未能减少更新，这表明这些区域内的突触前抑制本身可能不是驱动灭绝学习期间上下文特异性所必需的。总之，这些结果表明，突触前 GABA 受体在灭绝和更新过程中具有重要的性别依赖性作用，并确定了一种新的受体靶标，该靶标可能用于设计药理学疗法来增强暴露疗法的有效性。
