Abstract
BackgroundBehavioral 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/FindingsRats 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/SignificanceAcute 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.
Highlights
Behavioral stress is recognized as a main risk factor for many diseases, including cardiovascular, metabolic and neuropsychiatric diseases
While in HPC there were no changes, in prefrontal/ frontal cortex (P/FC) depolarization-evoked overflow of glutamate was markedly and significantly increased in stressed rats (52%; p,0.05, Student’s t test). This result was in line with previous findings of microdialysis studies [7,8,9,20], and suggested that acute FS-stress selectively increases the release of glutamate in P/FC, and does not affect glutamate release in HPC
In the present work we obtained evidence that acute stress induces a rapid rise of CORT levels, and that the potentiating effect of CORT on glutamate release in P/FC is mainly mediated by a glucocorticoid receptors (GR), similar to recent data obtained in prefrontal cortex (PFC) with different stressors [31]
Summary
Behavioral stress is recognized as a main risk factor for many diseases, including cardiovascular, metabolic and neuropsychiatric diseases. Among the latter, stress interacts with variable genetic background of vulnerability in pathogenesis of mood/anxiety disorders [1]. Inappropriate stress response acts as a trigger, which may produce a vulnerable phenotype in genetically predisposed individuals and increase the risk for mental ilness [2,3]. There is to date a lack of data on the management of acute stress and on possible treatments that may alleviate the distressing acute symptoms and prevent damaging long-term consequences [6]. Behavioral stress is recognized as a main risk factor for neuropsychiatric diseases. 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
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