Gom Renaud C, George Antis G, Harris Sydney A, Wickramarachchi Pasindu, Bhatt Dhyey, Acharjee Shaona, Pittman Quentin J, Hill Matthew N, Colangeli Roberto, Teskey G Campbell
Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
Neurobiol Stress. 2024 Oct 11;33:100678. doi: 10.1016/j.ynstr.2024.100678. eCollection 2024 Nov.
People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy. We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity. Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses. Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.
癫痫患者常常伴有精神疾病共病，这会显著损害他们的生活质量。我们之前报道过，反复的癫痫发作活动会持续改变杏仁核中的内源性大麻素（eCB）信号，这是大鼠共病情绪调节障碍的原因，然而，癫痫大脑中这些eCB信号变化发生的机制尚不清楚。内源性大麻素信号受皮质酮（CORT）影响，以调节认知和情绪过程，并且癫痫患者和癫痫非人类动物模型中均出现下丘脑-垂体-肾上腺（HPA）轴功能亢进。我们在杏仁核点燃的成年雄性Long-Evans大鼠中使用了选择性药理学工具和多种方法，包括全细胞膜片钳电生理学、行为范式和生化分析。我们旨在确定癫痫发作是否会诱导CORT分泌过多，以及这在eCB系统失调、恐惧记忆受损和与癫痫发作活动相关的焦虑样行为中所起的作用。在点燃过程中，癫痫发作后血浆CORT水平显著且持续升高。癫痫发作前给予CORT合成抑制剂美替拉酮可阻止这种癫痫发作诱导的CORT升高，防止杏仁核花生四烯酸乙醇胺下调以及癫痫发作活动诱导的突触改变。此外，在每次诱发癫痫发作前用美替拉酮或联合糖皮质激素受体（GR）/盐皮质激素受体（MR）拮抗剂进行治疗，在预防长期改变的焦虑样行为和恐惧记忆反应方面同样有效。抑制癫痫发作诱导的皮质酮合成，或直接在GR/MR处阻断CORT的作用，可防止情绪加工方面的有害变化，并且可能是治疗癫痫患者情绪共病的一种选择。
