Laboratory of Pharmacology, Neurobiology and Behavior, Faculty of Sciences Semlalia, Cadi Ayyad University, Bd. Prince My Abdallah, 40000, Marrakesh, Morocco.
Psychopharmacology (Berl). 2020 Aug;237(8):2451-2467. doi: 10.1007/s00213-020-05546-4. Epub 2020 May 19.
Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations. Most preclinical studies related to Topiramate have been focused exclusively on the quantitative aspects of the aggressive behavior between mice. However, there is still limited knowledge regarding the effects of Topiramate on neuronal mechanisms occurring in aggressive mice. The present work aims to understand further the effects of the antiepileptic drug Topiramate on aggressive behaviors, and on the neural correlates underlying such behaviors. To achieve this, we combined the resident-intruder model of isolation-induced aggression in mice with two drug regimens of Topiramate administration (30.0 mg/kg; acute and sub-chronic treatments). Our data showed that both acute and subchronic treatments decreased the intensity of agonistic encounters and reinforced social behavior. By using C-fos immunoreactivity, we investigated the neuronal activation of several brain regions involved in aggressive behavior following subchronic treatment. We found that Topiramate produced activation in several cortical areas and in the lateral septum of resident brain mice compared with their controls. However, Topiramate induced inhibition in the medial nucleus of the amygdala, the dorsomedial nucleus of the periaqueductal gray, and especially in the anterior hypothalamic nucleus. Finally, we performed microinfusion of Topiramate (0.1 and 0.3 mM) into the lateral septum and anterior hypothalamus on offensive behaviors in isolation-induced-aggression paradigm. Interestingly, the microinfusion of Topiramate into the lateral septum has the capacity to alleviate aggressive behavior, without affecting social behavior. However, the microinfusion of Topiramate into the anterior hypothalamus decreased aggressive behavior and slightly reinforced social behavior. Our observations supported that the dose of 0.1 mM of Topiramate appeared more efficacy to treat aggression in adult mice. These pharmacological characteristics may account for Topiramate efficacy on aggressive symptoms in psychiatric patients.
托吡酯是一种抗癫痫药物，已被发现可用于治疗临床人群的攻击行为。大多数与托吡酯相关的临床前研究都专门集中在小鼠之间攻击行为的定量方面。然而，关于托吡酯对攻击小鼠中神经元机制的影响，仍知之甚少。本研究旨在进一步了解抗癫痫药物托吡酯对攻击行为以及此类行为的神经相关性的影响。为此，我们将小鼠隔离诱导攻击的常驻入侵者模型与托吡酯给药的两种药物方案（30.0mg/kg；急性和亚慢性治疗）相结合。我们的数据表明，急性和亚慢性治疗均降低了攻击性行为的强度并增强了社会行为。通过使用 c-fos 免疫反应性，我们研究了亚慢性治疗后参与攻击性行为的几个大脑区域的神经元激活。我们发现，与对照组相比，托吡酯使常驻大脑小鼠的几个皮质区域和外侧隔核中的神经元激活。然而，托吡酯诱导了杏仁核内侧核、导水管周围灰质背内侧核的抑制，尤其是前下丘脑核的抑制。最后，我们在隔离诱导攻击范式中对侧隔核和前下丘脑进行了托吡酯（0.1 和 0.3mM）的微输注，以研究其对攻击行为的影响。有趣的是，托吡酯侧隔核内的微输注能够缓解攻击行为，而不影响社会行为。然而，托吡酯前下丘脑内的微输注降低了攻击行为，并略微增强了社会行为。我们的观察结果支持 0.1mM 托吡酯剂量似乎更有效地治疗成年小鼠的攻击行为。这些药理学特征可能解释了托吡酯对精神科患者攻击症状的疗效。
