van Staden Cailin, Weinshenker David, Finger-Baier Karin, Botha Tarryn L, Brand Linda, Wolmarans De Wet
Department of Pharmacology, Center of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
Behav Pharmacol. 2025 Feb 1;36(1):47-59. doi: 10.1097/FBP.0000000000000808. Epub 2024 Dec 24.
Traumatic stress exposure increases noradrenaline (NA) release, which contributes to anxiety and impaired risk-appraisal. Guanfacine, a selective alpha-2A adrenergic receptor agonist, has been used to treat stress-related disorders characterised by impaired prefrontal cortex function. By acting on both presynaptic inhibitory autoreceptors and postsynaptic heteroreceptors, guanfacine attenuates stress reactivity and enhances cognition. However, its effectiveness in treating trauma-related anxiety and risk-taking behaviour remains unclear. Leveraging the advantages of zebrafish (Danio rerio ) as a sensitive and efficient preclinical model which is ideal for stress research, we explored the impact of traumatic stress exposure combined with varying concentrations of guanfacine in adult zebrafish. Zebrafish were evaluated for trauma-related anxiety using both the novel tank test (NTT) and a novel version of the open-field test (nOFT), the latter which was also used to investigate risk-taking behaviour. We found that (1) traumatic stress exposure led to heightened risk-taking behaviour in the nOFT, and (2) low-to-moderate concentrations of guanfacine (3-20 µg/L) attenuated anxiety-like, but not risk-taking behaviour, with the highest concentration (40 µg/L), showing no effect. These results highlight the complex role of NA in modulating dysregulated behaviours during traumatic events and indicate the potential of guanfacine for improving trauma-related anxiety and risk-taking behaviour.
创伤应激暴露会增加去甲肾上腺素（NA）的释放，这会导致焦虑和风险评估受损。胍法辛是一种选择性α-2A肾上腺素能受体激动剂，已被用于治疗以额叶前皮质功能受损为特征的应激相关障碍。通过作用于突触前抑制性自身受体和突触后异源性受体，胍法辛可减轻应激反应并增强认知能力。然而，其在治疗创伤相关焦虑和冒险行为方面的有效性仍不明确。利用斑马鱼（Danio rerio）作为一种敏感且高效的临床前模型（非常适合应激研究）的优势，我们探究了创伤应激暴露与不同浓度胍法辛联合作用对成年斑马鱼的影响。使用新鱼缸试验（NTT）和一种新型旷场试验（nOFT）对斑马鱼的创伤相关焦虑进行评估，后者也用于研究冒险行为。我们发现：（1）创伤应激暴露导致nOFT中的冒险行为增加；（2）低至中等浓度的胍法辛（3 - 20μg/L）可减轻类似焦虑的行为，但对冒险行为无效，最高浓度（40μg/L）则无效果。这些结果突出了NA在调节创伤事件期间失调行为中的复杂作用，并表明胍法辛在改善创伤相关焦虑和冒险行为方面的潜力。
