Ribeiro Fernanda Teixeira, de Serro-Azul Marcia Ivany Silva, Lorena Fernanda Beraldo, do Nascimento Bruna Pascarelli Pedrico, Arnold Alexandre José Tavolari, Barbosa Geraldo Henrique Lemos, Ribeiro Miriam Oliveira, Cysneiros Roberta Monterazzo
Developmental Disabilities Postgraduate Program, Laboratory of Neurobiology and Metabolism, Mackenzie Presbyterian University, São Paulo, Brazil.
Postgraduate Program in Translational Medicine, Federal University of São Paulo, São Paulo, Brazil.
Front Behav Neurosci. 2020 Dec 9;14:560423. doi: 10.3389/fnbeh.2020.560423. eCollection 2020.
The early life (SE) causes high anxiety and chronic socialization abnormalities, revealed by a low preference for social novelty and deficit in social discrimination. This study investigated the involvement of the endocannabinoid system on the sociability in this model, due to its role in social motivation regulation. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE and controls received saline. From P60 the groups received vehicle or JZL195 2 h before each behavioral test to increase endocannabinoids availability. In the sociability test, animals subjected to neonatal SE exhibited impaired sociability, characterized by social discrimination deficit, which was unaffected by the JZL195 treatment. In contrast, JZL195-treated control rats showed low sociability and impaired social discrimination. The negative impact of JZL195 over the sociability in control rats and the lack of effect in animals subjected to neonatal SE was confirmed in the social memory paradigm. In this paradigm, as expected for vehicle-treated control rats, the investigation toward the same social stimulus decreased with the sequential exposition and increased toward a novel stimulus. In animals subjected to neonatal SE, regardless of the treatment, as well as in JZL195-treated control rats, the investigation toward the same social stimulus was significantly reduced with no improvement toward a novel stimulus. Concerning the locomotion, the JZL195 increased it only in control rats. After behavioral tests, brain tissues of untreated animals were used for CB1 receptor quantification by Elisa and for gene expression by RT-PCR: no difference between control and experimental animals was noticed. The results reinforce the evidence that the early causes chronic socialization abnormalities, revealed by the low social interest for novelty and impaired social discrimination. The dual FAAH/MAGL inhibitor (JZL195) administration before the social encounter impaired the social interaction in intact rats with no effect in animals subjected to early-life seizures.
早期生活应激（SE）会导致高度焦虑和慢性社交异常，表现为对社交新奇性的偏好较低以及社交辨别能力缺陷。由于内源性大麻素系统在社会动机调节中的作用，本研究调查了该系统在该模型社交能力中的参与情况。出生后第9天的雄性Wistar大鼠接受毛果芸香碱诱导的新生儿期SE，对照组接受生理盐水。从出生后第60天起，每组在每次行为测试前2小时接受载体或JZL195以增加内源性大麻素的可用性。在社交能力测试中，经历新生儿期SE的动物表现出社交能力受损，其特征为社交辨别缺陷，JZL195治疗对此无影响。相比之下，接受JZL195治疗的对照大鼠表现出社交能力低下和社交辨别受损。在社会记忆范式中证实了JZL195对对照大鼠社交能力的负面影响以及对经历新生儿期SE的动物无效。在该范式中，正如载体治疗的对照大鼠所预期的那样，随着对同一社交刺激的连续暴露，对其的探究减少，而对新刺激的探究增加。在经历新生儿期SE的动物中，无论治疗如何，以及在接受JZL195治疗의对照大鼠中，对同一社交刺激的探究均显著减少，对新刺激没有改善。关于运动能力，JZL195仅在对照大鼠中增加了运动能力。行为测试后，未治疗动物的脑组织用于通过酶联免疫吸附测定法（Elisa）进行CB1受体定量以及通过逆转录聚合酶链反应（RT-PCR）进行基因表达：未发现对照动物和实验动物之间存在差异。结果强化了以下证据，即早期应激会导致慢性社交异常，表现为对新奇事物的社交兴趣低和社交辨别受损。在社交接触前给予双重脂肪酸酰胺水解酶/单酰甘油脂肪酶抑制剂（JZL195）会损害完整大鼠的社交互动，而对经历早期癫痫发作的动物没有影响。
