Department of Psychiatry, Columbia University Irving Medical Center, New York, New York; Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York; Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal.
Neurobiology and Behavior Graduate Program, Columbia University, New York, New York.
Biol Psychiatry. 2021 Jun 15;89(12):1150-1161. doi: 10.1016/j.biopsych.2021.01.005. Epub 2021 Jan 20.
Posttraumatic stress disorder can develop after a traumatic event and results in heightened, inappropriate fear and anxiety. Although approximately 8% of the U.S. population is affected by posttraumatic stress disorder, only two drugs have been approved by the Food and Drug Administration to treat it, both with limited efficacy. Propranolol, a nonselective β-adrenergic antagonist, has shown efficacy in decreasing exaggerated fear, and there has been renewed interest in using it to treat fear disorders.
Here, we sought to determine the mechanisms by which propranolol attenuates fear by utilizing an activity-dependent tagging system, ArcCreER x eYFP mice. 129S6/SvEv mice were administered a 4-shock contextual fear conditioning paradigm followed by immediate or delayed context reexposures. Saline or propranolol was administered either before or after the first context reexposure. To quantify hippocampal, prefrontal, and amygdalar memory traces, ArcCreER x eYFP mice were administered a delayed context reexposure with either a saline or propranolol injection before context reexposure.
Propranolol decreased fear expression only when administered before a delayed context reexposure. Fear memory traces were affected in the dorsal dentate gyrus and basolateral amygdala after propranolol administration in the ArcCreER x eYFP mice. Propranolol acutely altered functional connectivity between the hippocampal, cortical, and amygdalar regions.
These data indicate that propranolol may decrease fear expression by altering network-correlated activity and by weakening the reactivation of the initial traumatic memory trace. This work contributes to the understanding of noradrenergic drugs as therapeutic aids for patients with posttraumatic stress disorder.
创伤后应激障碍可在创伤事件后发生，并导致过度、不适当的恐惧和焦虑。尽管美国约有 8%的人口受到创伤后应激障碍的影响，但仅有两种药物被食品和药物管理局批准用于治疗该疾病，且疗效均有限。非选择性β肾上腺素能拮抗剂普萘洛尔已显示出降低过度恐惧的疗效，因此人们重新产生了使用它来治疗恐惧障碍的兴趣。
在这里，我们试图通过利用一种活性依赖性标记系统，ArcCreER x eYFP 小鼠，确定普萘洛尔减轻恐惧的机制。将 129S6/SvEv 小鼠给予 4 次冲击情境性恐惧条件反射范式，随后立即或延迟进行情境再暴露。在第一次情境再暴露之前或之后给予生理盐水或普萘洛尔。为了量化海马体、前额叶和杏仁核的记忆痕迹，ArcCreER x eYFP 小鼠在进行延迟的情境再暴露之前，给予生理盐水或普萘洛尔注射。
只有在延迟的情境再暴露之前给予普萘洛尔时，才能降低恐惧表达。在普萘洛尔给药后，ArcCreER x eYFP 小鼠的背齿状回和基底外侧杏仁核中的恐惧记忆痕迹受到影响。普萘洛尔急性改变了海马体、皮质和杏仁核区域之间的功能连接。
这些数据表明，普萘洛尔可能通过改变网络相关的活动和削弱初始创伤性记忆痕迹的再激活来降低恐惧表达。这项工作有助于理解去甲肾上腺素能药物作为创伤后应激障碍患者的治疗辅助手段。
