Kogan Natalya M, Begmatova Dilorom, Vinnikova Liudmila, Malitsky Sergey, Itkin Maxim, Sharon Eyal, Klinov Artem, Gorelick Jonathan, Koman Igor, Vogel Zvi, Mechoulam Raphael, Pinhasov Albert
Department of Molecular Biology, Ariel University, Ariel, Israel.
The Institute of Personalized and Translational Medicine, Ariel University, Ariel, Israel.
Front Pharmacol. 2023 Aug 16;14:1234332. doi: 10.3389/fphar.2023.1234332. eCollection 2023.
The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness. A lipidomics approach was employed to assess the endocannabinoidome in the brains of Dominant (Dom) and Submissive (Sub) mice. The endocannabinoid showing the greatest difference in concentration in the brain between the groups, docosatetraenoyl ethanolamine (DEA), was synthesized, and its effects on the physiological and behavioral responses of Dom and Sub mice were evaluated. mRNA expression of the endocannabinoid receptors and enzymes involved in PUFA biosynthesis was assessed using qRT-PCR. Targeted LC/MS analysis revealed that long-chain polyunsaturated ethanolamides including arachidonoyl ethanolamide (AEA), DEA, docosatrienoyl ethanolamide (DTEA), eicosatrienoyl ethanolamide (ETEA), eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) were higher in the Sub compared with the Dom mice. Untargeted LC/MS analysis showed that the parent fatty acids, docosatetraenoic (DA) and eicosapentaenoic (EPA), were higher in Sub vs. Dom. Gene expression analysis revealed increased mRNA expression of genes encoding the desaturase FADS2 and the elongase ELOVL5 in Sub mice compared with Dom mice. Acute DEA administration at the dose of 15 mg/kg produced antinociceptive and locomotion-inducing effects in Sub mice, but not in Dom mice. Subchronic treatment with DEA at the dose of 5 mg/kg augmented dominant behavior in wild-type ICR and Dom mice but not in Sub mice. This study suggests that the endocannabinoid system may play a role in the regulation of dominance and submissiveness, functional elements of social behavior and personality. While currently we have only scratched the surface, understanding the role of the endocannabinoid system in personality may help in revealing the mechanisms underlying the etiopathology of psychiatric disorders.
内源性大麻素系统被认为与学习、记忆、情绪处理以及人格模式的调节有关。在此，我们评估了具有强烈社会主导和顺从特征的小鼠大脑中的内源性大麻素谱。采用脂质组学方法评估优势（Dom）小鼠和顺从（Sub）小鼠大脑中的内源性大麻素组。合成了两组小鼠大脑中浓度差异最大的内源性大麻素二十二碳四烯酰乙醇胺（DEA），并评估了其对Dom和Sub小鼠生理和行为反应的影响。使用qRT-PCR评估参与多不饱和脂肪酸（PUFA）生物合成的内源性大麻素受体和酶的mRNA表达。靶向液相色谱/质谱分析显示，与Dom小鼠相比，Sub小鼠中包括花生四烯酰乙醇胺（AEA）、DEA、二十二碳三烯酰乙醇胺（DTEA）、二十碳三烯酰乙醇胺（ETEA）、二十碳五烯酰乙醇胺（EPEA）和二十二碳六烯酰乙醇胺（DHEA）在内的长链多不饱和乙醇酰胺含量更高。非靶向液相色谱/质谱分析表明，Sub小鼠中母体脂肪酸二十二碳四烯酸（DA）和二十碳五烯酸（EPA）的含量高于Dom小鼠。基因表达分析显示，与Dom小鼠相比，Sub小鼠中编码去饱和酶FADS2和延长酶ELOVL5的基因的mRNA表达增加。以15mg/kg的剂量急性给予DEA对Sub小鼠产生了抗伤害感受和诱导运动的作用，但对Dom小鼠没有作用。以5mg/kg的剂量对DEA进行亚慢性治疗增强了野生型ICR小鼠和Dom小鼠的主导行为，但对Sub小鼠没有作用。这项研究表明，内源性大麻素系统可能在调节主导和顺从方面发挥作用，主导和顺从是社会行为和人格的功能要素。虽然目前我们只是触及了表面，但了解内源性大麻素系统在人格中的作用可能有助于揭示精神疾病病因学的潜在机制。
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