Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
Department of Biological Sciences, School of Science, Humanities and Languages, São Paulo State University (UNESP), Assis, São Paulo, Brazil.
Psychopharmacology (Berl). 2022 Sep;239(9):2753-2769. doi: 10.1007/s00213-022-06127-3. Epub 2022 Jun 2.
The endocannabinoid modulation of fear and anxiety due to the on-demand synthesis and degradation is supported by a large body of research. Although it has been proposed that anandamide (AEA) in the substantia nigra pars reticulata (SNpr) seems to be important for the organisation of innate fear-related behaviours, a role for endogenous AEA has yet to be clarified.
Mice were treated with the fatty acid amide hydrolase (FAAH) selective inhibitor URB597 at different concentrations (0.01, 0.1, 1 nmol/0.1 µL) in the SNpr and confronted by rattlesnakes (Crotalus durissus terrificus). The most effective dose of URB597 (1 nmol) was also preceded by microinjections of the CB receptor antagonist AM251 (0.1 nmol) into the SNpr, and mice were then confronted by the venomous snake.
URB597 (0.1 and 1 nmol) in the SNpr decreased the expression of defensive behaviours such as defensive attention, escape, and time spent inside the burrow of mice confronted by rattlesnakes. Moreover, pretreatment of SNpr with AM251 suppressed these antiaversive effects of URB597 in this midbrain structure.
Overall, these data clearly indicate that the panicolytic consequences of endogenous AEA enhancement in the SNpr are mediated by CB1 receptor signalling.
由于按需合成和降解，内源性大麻素对恐惧和焦虑的调节得到了大量研究的支持。尽管已经提出，中脑网状部（SNpr）中的花生四烯酸乙醇酰胺（AEA）似乎对于先天恐惧相关行为的组织很重要，但内源性 AEA 的作用尚未得到阐明。
用脂肪酸酰胺水解酶（FAAH）选择性抑制剂 URB597 在 SNpr 以不同浓度（0.01、0.1、1 nmol/0.1 µL）处理小鼠，然后让其面对响尾蛇（Crotalus durissus terrificus）。URB597 的最有效剂量（1 nmol）之前也在 SNpr 中预先注射了 CB 受体拮抗剂 AM251（0.1 nmol），然后让小鼠面对毒蛇。
SNpr 中的 URB597（0.1 和 1 nmol）降低了面对响尾蛇的小鼠的防御行为（如防御性注意、逃避和在洞穴内的时间）的表达。此外，SNpr 中的 AM251 预处理抑制了 URB597 在该中脑结构中的这些抗厌恶作用。
总体而言，这些数据清楚地表明，SNpr 中内源性 AEA 增强的惊恐缓解作用是由 CB1 受体信号介导的。
