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 
. Exposure of rodents to various stress protocols produces many behavioral, neurochemical, neuroendocrine, concomitants observed in humans 
. While animals subjected to chronic stress paradigms are often used as models of psychiatric pathology, it is also important to study the brain response to acute stress, because this may be particularly helpful in dissecting the molecular and cellular mechanisms involved 
. Acute stress induces rapid changes in the release of neurotransmitters, hormones and cytokines that are adaptive, but may become damaging if the stress response is inadequate or excessive. Inappropriate stress response acts as a trigger, which may produce a vulnerable phenotype in genetically predisposed individuals and increase the risk for mental ilness 
. 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 
. It should also be considered that the effects of chronic stress are not simply an extrapolation of the effects of acute stress, and complex adaptive phenomena must be taken into account in the long run.
A number of studies have suggested that acute stress is associated with increased excitatory amino acid transmission in areas of the forebrain. Restraint stress, tail pinch, forced swimming, footshock, and anxiogenic drugs have been shown to increase the efflux of glutamate as measured by microdialysis in vivo 
. However, although it is assumed that behavioral stressors can deeply affect homeostasis of glutamate transmission, it is not yet clear:
- What is the effect of acute stress on exocytotic release of glutamate in limbic/cortical areas. Thus far this has been assessed mainly or exclusively by in vivo microdialysis. However, it has been argued that extracellular glutamate and GABA, as measured by microdialysis, do not fulfill the classical criteria for exocytotic release (tetrodotoxin sensitivity, calcium-dependency). Accordingly, a large portion of amino acid neurotransmitters measured by this way may be of non-neuronal origin and possibly carrier-mediated or derived from glial metabolism . Independent evidence (not from microdialysis) would be helpful to verify the outcome of acute stress on glutamate release and transmission.
- What are the mechanisms whereby acute stress modifies glutamate release. Recent work has shown that stress rapidly increases the level of circulating stress-hormones and that in hippocampus (HPC) corticosterone (CORT) binds to membrane mineralocorticoid receptors (MR), which may rapidly induce the release of glutamate through non-transcriptional mechanisms , . It is not known at present what changes in the mechanisms regulating glutamate release are affected by CORT.
- What is the effect of psychotropics used for therapy of psychiatric disorders on the release of glutamate. A few studies have suggested that chronic antidepressant treatments reduce glutamate release in limbic/cortical areas in basal conditions –. In particular, we have found previously that chronic antidepressants reduce (K+)depolarization-evoked release of endogenous glutamate from synaptic terminals of HPC, with concomitant modifications in protein-protein interactions regulating assembly of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex, that mediates fusion of synaptic vesicles, and reduction of complexes in presynaptic membranes , .
Here we found that acute footshock (FS)-stress up-regulates depolarization-evoked exocytotic glutamate release in prefrontal/frontal cortex (P/FC) but not HPC, by increasing the circulating levels of CORT, stimulating glucocorticoid receptors (GR) in P/FC, and inducing accumulation of SNARE complexes in presynaptic membranes. Moreover, analysis of excitatory postsynaptic currents (EPSCs) in pyramidal neurons of the prefrontal cortex (PFC), showed that stress induced dramatic changes in paired-pulse facilitation (PPF) and a slowdown of the EPSC kinetics, suggestive of both pre- and postsynaptic actions. Previous chronic administration of different antidepressants completely prevented the stress-induced up-regulation of glutamate release by a mechanism downstream of the elevation of CORT and SNARE complex accumulation, which involves a decrease in release probability.