Department of Pharmacological Sciences, Center of Neuropharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milano, Italy.
PLoS One. 2010 Jan 5;5(1):e8566. doi: 10.1371/journal.pone.0008566.
Behavioral stress is recognized as a main risk factor for neuropsychiatric diseases. Converging evidence suggested that acute stress is associated with increase of excitatory transmission in certain forebrain areas. Aim of this work was to investigate the mechanism whereby acute stress increases glutamate release, and if therapeutic drugs prevent the effect of stress on glutamate release.
METHODOLOGY/FINDINGS: Rats were chronically treated with vehicle or drugs employed for therapy of mood/anxiety disorders (fluoxetine, desipramine, venlafaxine, agomelatine) and then subjected to unpredictable footshock stress. Acute stress induced marked increase in depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex in superfusion, and the chronic drug treatments prevented the increase of glutamate release. Stress induced rapid increase in the circulating levels of corticosterone in all rats (both vehicle- and drug-treated), and glutamate release increase was blocked by previous administration of selective antagonist of glucocorticoid receptor (RU 486). On the molecular level, stress induced accumulation of presynaptic SNARE complexes in synaptic membranes (both in vehicle- and drug-treated rats). Patch-clamp recordings of pyramidal neurons in the prefrontal cortex revealed that stress increased glutamatergic transmission through both pre- and postsynaptic mechanisms, and that antidepressants may normalize it by reducing release probability.
CONCLUSIONS/SIGNIFICANCE: Acute footshock stress up-regulated depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex. Stress-induced increase of glutamate release was dependent on stimulation of glucocorticoid receptor by corticosterone. Because all drugs employed did not block either elevation of corticosterone or accumulation of SNARE complexes, the dampening action of the drugs on glutamate release must be downstream of these processes. This novel effect of antidepressants on the response to stress, shown here for the first time, could be related to the therapeutic action of these drugs.
行为应激被认为是神经精神疾病的主要风险因素。越来越多的证据表明，急性应激与某些前脑区域兴奋性传递的增加有关。本研究旨在探讨急性应激增加谷氨酸释放的机制，以及治疗药物是否能预防应激对谷氨酸释放的影响。
方法/发现：大鼠长期接受 vehicle 或用于治疗情绪/焦虑障碍的药物（氟西汀、去甲丙咪嗪、文拉法辛、阿戈美拉汀）治疗，然后进行不可预测的足底电击应激。急性应激诱导突触体从前额/额叶皮质的去极化诱发释放谷氨酸显著增加，而慢性药物治疗可预防谷氨酸释放的增加。应激诱导所有大鼠（vehicle 和药物处理组）的循环皮质酮水平迅速增加，而糖皮质激素受体选择性拮抗剂（RU 486）可阻断谷氨酸释放的增加。在分子水平上，应激诱导突触膜中突触前 SNARE 复合物的积累（vehicle 和药物处理组大鼠均如此）。在额皮质的锥体神经元的膜片钳记录显示，应激通过前突触和后突触机制增加谷氨酸能传递，而抗抑郁药可能通过降低释放概率来使谷氨酸能传递正常化。
结论/意义：急性足底电击应激增加了前额/额叶皮质突触体的去极化诱发释放谷氨酸。应激诱导的谷氨酸释放增加依赖于皮质酮对糖皮质激素受体的刺激。由于所使用的所有药物都不能阻断皮质酮的升高或 SNARE 复合物的积累，因此这些药物对谷氨酸释放的抑制作用必须发生在这些过程的下游。抗抑郁药对应激反应的这种新作用，在此首次显示，可能与这些药物的治疗作用有关。
