The endocannabinoid effect on sociability

Early life seizures in rodents leads to autistic-like behavior, characterized by low preference for novelty, deficit in social recognition and high anxiety. We used this animal model to better understand the role of the endocannabinoid system on sociability. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal status epilepticus and controls received saline. From P60 groups received vehicle or JZL195 2 hours prior each behavioral test, in order to increase endocannabinoids availability. In social discrimination test, untreated control animals spent higher time with social novelty as compared to familiar one (t= 3.263; p<0.01). The JZL195 reduced the overall time spent with the conspecifics (F(1,19)=6.11; p=0.023) and also inhibited the social discrimination (t=0.17; p>0.05). In this paradigm, the significant interaction between factors (conspecific x treatment) (F(1,19)= 4.863;p=0.04) suggests that control animals under JZL195 effect exhibited reduced social motivation. In contrast, the untreated experimental group did not show preference for social novelty (t= 0.336; p>0.05) and JZL195 did not modify the impaired social discrimination. In social recognition test, control animals, regardless the treatment, showed habituation to the social stimulus (F(2,32)= 11.64, p=0.0002), suggesting that animals exhibited social recognition memory, but it was reduced by the treatment with JZL 195 (F(1,16)= 5.086, p= 0.038). Moreover, time of investigation increased when the familiar social stimulus was replaced by new one (F(1,16)=10.24, p=0.005), suggesting that social memory recognition was preserved. Treated control animals exhibited a lower time of investigation toward social stimulus (F(1,16)=9.092, p=0.0082), suggesting that JZL195 reduced the social motivation without affect social recognition memory. In the experimental group, the time of investigation decreased when exposed to the same animal (F (2,34)=7.92, p=0.0015), suggestive that the social recognition was preserved and unaffected by the treatment with JZL195 (F(1,17)= 0.246; n.s). The JZL195 decreased the time of investigation only in control group (t=2.464, p= 0.025) to values that are similar to the experimental one. After behavioral tests, brain tissues were used for CB1 receptor quantification by Elisa and for gene expression by RT-PCR: no difference between control and experimental animals was detected. Our results state that increased endocannabinoid signaling reduces social motivation in intact rats and has no effect in animals submitted to early life seizures.

在啮齿动物早期生活期发生的癫痫发作导致自闭症样行为，其特征为对新颖事物的偏好降低、社会识别能力缺陷以及焦虑水平升高。本研究采用此动物模型，旨在深入了解内源性大麻素系统在社会交往中的作用。在出生后第9天，雄性Wistar大鼠接受了毛果芸香碱诱导的新生儿癫痫持续状态，而对照组则接受生理盐水。从P60开始，两组动物在行为测试前2小时分别给予溶剂或JZL195，以增加内源性大麻素的可利用性。在社会辨别测试中，未经治疗的对照组动物相较于熟悉对象，花费更多时间与陌生社会对象相处（t=3.263；p<0.01）。JZL195降低了与同种动物的总体相处时间（F(1,19)=6.11；p=0.023），并抑制了社会辨别（t=0.17；p>0.05）。在此范式下，因素间（同种动物 x 治疗）的显著交互作用（F(1,19)=4.863；p=0.04）表明，在JZL195的作用下，对照组动物的社会动机有所降低。相反，未经治疗的实验组未表现出对社会新颖性的偏好（t=0.336；p>0.05），而JZL195并未改变受损的社会辨别。在社会识别测试中，无论是否接受治疗，对照组动物均表现出对社交刺激的习惯化（F(2,32)=11.64，p=0.0002），表明动物表现出社会识别记忆，但经JZL 195治疗后有所降低（F(1,16)=5.086，p=0.038）。此外，当将熟悉的社会刺激替换为新的刺激时，探究时间增加（F(1,16)=10.24，p=0.005），表明社会记忆识别得到保留。接受治疗的对照组动物对社交刺激的探究时间较低（F(1,16)=9.092，p=0.0082），表明JZL195降低了社会动机，但未影响社会识别记忆。在实验组中，当接触相同的动物时，探究时间减少（F(2,34)=7.92，p=0.0015），提示社会识别得到保留且未受JZL195治疗的影响（F(1,17)=0.246；n.s）。JZL195仅降低了对照组的探究时间（t=2.464，p=0.025），降至与实验组相似的水平。在行为测试后，脑组织被用于通过Elisa法进行CB1受体定量和通过RT-PCR进行基因表达分析：对照组和实验组之间未检测到差异。我们的结果表明，增加的内源性大麻素信号降低了完整大鼠的社会动机，而对早期生活期癫痫发作的动物则无影响。