Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China.
Neuropharmacology. 2020 Dec 15;181:108361. doi: 10.1016/j.neuropharm.2020.108361. Epub 2020 Oct 21.
Topiramate is an approved antiepileptic drug clinically used to treat epilepsy and prevent migraines. Currently, topiramate has been found to be effective in treating aggressive symptoms in neuropsychiatric patients. In preclinical studies, however, the effects and mechanisms of topiramate on offensive aggression are still largely uninvestigated. Our previous studies indicated that glutamatergic transmission in the ventrolateral periaqueductal gray (vlPAG) plays a crucial role in regulating elements of offensive aggressive behaviors. In the present work, we investigated the actions of topiramate on vlPAG glutamatergic transmission and aggressive behaviors in group-housed (GH) and socially isolated (SI) rats. The results suggested that a single injection of topiramate systemically and dose-dependently inhibited elements of offensive aggressive behaviors of both GH and SI rats in the resident-intruder test (RIT), with long-lasting effective time profiles in SI rats. Moreover, systemic single administration of topiramate reduced the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Bath perfusion of topiramate directly decreased the frequency and amplitude of mEPSCs and shortened the amplitude of evoked excitatory postsynaptic currents (EPSCs) in the vlPAG. Furthermore, intra-vlPAG single microinjection of topiramate dose-dependently inhibited offensive aggressive behaviors in GH and SI rats in a time-dependent manner. Additionally, both systemic and local topiramate inhibited offensive aggressive behaviors in a (2R,6R)-hydroxynorketamine (HNK)-dependent rat model. In conclusion, the present results suggest that topiramate exerts anti-aggressive roles through its inhibitory actions on glutamatergic activities in the vlPAG. These preclinical results support topiramate as a candidate drug to treat patients with heightened offensive aggression.
托吡酯是一种已被批准的抗癫痫药物，临床上用于治疗癫痫和预防偏头痛。目前，已发现托吡酯在治疗神经精神科患者的攻击性行为方面有效。然而，在临床前研究中，托吡酯对攻击性行为的影响和机制仍在很大程度上尚未得到研究。我们之前的研究表明，腹外侧导水管周围灰质（vlPAG）中的谷氨酸能传递在调节攻击性行为的要素中起着关键作用。在本工作中，我们研究了托吡酯对群居（GH）和社会隔离（SI）大鼠 vlPAG 谷氨酸能传递和攻击性行为的作用。结果表明，单次系统注射托吡酯可剂量依赖性地抑制 GH 和 SI 大鼠在居民-入侵者测试（RIT）中的攻击性行为要素，在 SI 大鼠中具有持久的有效时间曲线。此外，系统单次给予托吡酯可降低 vlPAG 中小兴奋性突触后电流（mEPSC）的频率和幅度。托吡酯的灌流直接降低了 vlPAG 中小兴奋性突触后电流（mEPSC）的频率和幅度，并缩短了诱发兴奋性突触后电流（EPSC）的幅度。此外，vlPAG 内单次微注射托吡酯可时间依赖性地抑制 GH 和 SI 大鼠的攻击性行为，呈剂量依赖性。此外，全身和局部托吡酯均可抑制（2R，6R）-羟基去甲氯胺（HNK）依赖性大鼠模型中的攻击性行为。总之，本研究结果表明，托吡酯通过抑制 vlPAG 中的谷氨酸能活性发挥抗攻击作用。这些临床前结果支持托吡酯作为治疗攻击性行为增强患者的候选药物。
