Istituto di Ricovero e Cura a Carattere Scientifico, Centro Neurolesi "Bonino-Pulejo," Messina 98124, Italy, Neural Plasticity Team-Unité Mixte de Recherche 8576 Centre National de la Recherche Scientifique/Université Lille 1, Department of Structural and Functional Glycobiology, F-59655 Villeneuve d'Ascq, France, Institutes de Recherches Internationales Servier, 92150 Suresnes, France, Department of Pharmacy, University of Genoa, Genoa 16146, Italy, Sapienza University of Rome and Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli 86077, Italy, and International Associated Laboratory-Prenatal Stress and Neurodegenerative Diseases, F-59655 Villeneuve d'Ascq, IT-00185 Rome, IT-86077 Pozzilli.
J Neurosci. 2014 Feb 5;34(6):2015-24. doi: 10.1523/JNEUROSCI.4131-13.2014.
Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related disorders in the adult life. Rats exposed to prenatal restraint stress (PRS) develop enduring biochemical and behavioral changes characteristic of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions. We have recently demonstrated a causal link between the reduction of glutamate release in the ventral hippocampus and anxiety-like behavior in PRS rats. To confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders, we examined whether chronic treatment with two antidepressants with different mechanisms of action could correct the defect in glutamate release and associated behavioral abnormalities in PRS rats. Adult unstressed or PRS rats were treated daily with either agomelatine (40 mg/kg, i.p.) or fluoxetine (5 mg/kg, i.p.) for 21 d. Both treatments reversed the reduction in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of PRS rats. Antidepressant treatment also corrected abnormalities in anxiety-/depression-like behavior and social memory performance in PRS rats. The effect on glutamate release was strongly correlated with the improvement of anxiety-like behavior and social memory. These data offer the pharmacological demonstration that glutamatergic hypofunction in the ventral hippocampus lies at the core of the pathological phenotype caused by early life stress and represents an attractive pharmacological target for novel therapeutic strategies.
海马体突触传递的异常是早期生活应激引发的编程改变的一个组成部分，这增加了成年后应激相关障碍的易感性。暴露于产前束缚应激（PRS）的大鼠会发展出持久的生化和行为变化，表现出焦虑/抑郁样表型。PRS 大鼠的大多数神经化学异常发生在腹侧海马体，这是一个编码与应激和情绪相关的记忆的区域。我们最近证明了腹侧海马体谷氨酸释放减少与 PRS 大鼠的焦虑样行为之间存在因果关系。为了赋予应激相关障碍的谷氨酸能假说以药理学有效性，我们研究了两种具有不同作用机制的抗抑郁药的慢性治疗是否可以纠正 PRS 大鼠中谷氨酸释放缺陷和相关的行为异常。成年未应激或 PRS 大鼠每天接受阿莫沙平（40mg/kg，腹腔注射）或氟西汀（5mg/kg，腹腔注射）治疗 21 天。两种治疗都逆转了 PRS 大鼠腹侧海马体去极化诱发的谷氨酸释放减少和突触囊泡相关蛋白表达的减少。抗抑郁治疗还纠正了 PRS 大鼠的焦虑/抑郁样行为和社交记忆表现异常。谷氨酸释放的改善与焦虑样行为和社交记忆的改善密切相关。这些数据提供了药理学证据，表明腹侧海马体的谷氨酸能功能低下是早期生活应激引起的病理表型的核心，代表了一种有吸引力的药理学治疗靶点，用于新的治疗策略。
