Laboratory of Translational Behavioural Neuroscience, Department of Behavioural Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, Budapest 1083, Hungary; Janos Szentagothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
Laboratory of Behavioural and Stress Studies, Department of Behavioural Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:84-91. doi: 10.1016/j.pnpbp.2018.11.007. Epub 2018 Nov 17.
Endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were shown to be involved in the basis of trauma-induced behavioral changes, particularly contextual conditioned fear, however, their ligand-specific effects and possible interactions are poorly understood. Here we assessed specific eCB effects and interactions on acquisition of contextual conditioned fear employing electric footshocks in a rat model. We selectively increased eCB levels by pharmacological blockade of the degrading enzymes of AEA by URB597 and 2-AG by JZL184 before traumatization either systemically or locally in relevant brain areas, the prelimbic cortex (PrL), ventral hippocampus (vHC) and basolateral amygdala (BLA). Following traumatization, a series of contextual reminders were conducted during which conditioned fear was assessed. While systemic URB597-treatment during traumatization only slightly enhanced the acquisition of contextual conditioned fear, administration of the compound in the PrL and vHC led to the acquisition of stable, lasting conditioned fear, resistant to extinction. These effects of URB597 were blocked by simultaneous administration of JZL184. Similar treatment effects did not occur in the BLA. Treatment effects were not secondary to alterations in locomotor activity or nociception. Our findings suggest that AEA and 2-AG functionally interact in the regulation of acquisition of contextual conditioned fear. AEA signaling in the PrL and vHC is a crucial promoter of fear acquisition while 2-AG potentially modulates this effect. The lack of eCB effects in the BLA suggests functional specificity of eCBs at distinct brain sites.
内源性大麻素（eCBs），如花生四烯酸乙醇胺（AEA）和 2-花生四烯酸甘油（2-AG），被证明参与了创伤引起的行为变化的基础，特别是情境条件性恐惧，但它们的配体特异性效应和可能的相互作用还知之甚少。在这里，我们评估了特定的 eCB 效应及其在大鼠模型中电击足底伤后情境条件性恐惧获得过程中的相互作用。我们通过药理学方法选择性地增加了 eCB 水平，即通过 URB597 阻断 AEA 的降解酶，通过 JZL184 阻断 2-AG 的降解酶，分别在创伤前全身或相关脑区（额前皮质，PrL；海马腹侧部，vHC；基底外侧杏仁核，BLA）进行局部给药。创伤后，进行了一系列的情境提示，在此期间评估了条件性恐惧。虽然创伤期间全身给予 URB597 治疗仅略微增强了情境条件性恐惧的获得，但在 PrL 和 vHC 中给予该化合物则导致了稳定、持久的条件性恐惧的获得，且不易消退。URB597 的这些作用被同时给予 JZL184 所阻断。在 BLA 中没有发生类似的治疗效果。治疗效果不是由于运动活动或疼痛感知的改变引起的。我们的发现表明，AEA 和 2-AG 在调节情境条件性恐惧的获得中具有功能相互作用。AEA 在 PrL 和 vHC 中的信号传导是恐惧获得的关键促进剂，而 2-AG 可能调节这种效应。在 BLA 中没有 eCB 作用表明 eCB 在不同脑区具有功能特异性。
