Acute Stress Increases Depolarization-Evoked Glutamate Release in the Rat Prefrontal/Frontal Cortex: The Dampening Action of Antidepressants

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.

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…A rise in peripheral corticosterone levels produces a rapid increase in corticosterone levels in the hippocampus in parallel with a specific increase in extracellular glutamate levels [18]. Glucocorticoid-induced increases in extracellular glutamate levels in the hippocampus can be exerted through a variety of mechanisms, including GR-mediated inhibition of glutamate uptake [19,20] and non-genomic membrane MR-or GR-mediated increase of presynaptic glutamate release probability [21][22][23][24]; nevertheless it should also be noted that a GR-mediated decrease in glutamate release probability has been observed in some brain regions such the hypothalamus [25]. However, for this mechanism to be effective it should ideally be capable of affecting excitatory transmission immediately (Figure 1a,b).…”

Glutamate hypothesis of depression and its consequences for antidepressant treatments

“…In this context, a pharmacological modulation of presynaptic release of glutamate might provide a means of attenuating exaggerated or inadequate stress response in mood/anxiety disorders. On the other hand, since several antidepressants tested, endowed with distinct primary mechanisms, are all able to abolish the effects of stress on glutamate release [15], we hypothesize that this could be a selective property of antidepressants related with their therapeutic action. For this reason, we propose the measurement of the preventive effect of drugs on stress-induced glutamate release as a functional test to assay molecules with antidepressant/anxiolytic action.…”

“…Indeed, a number of studies reported a rapid, transient and marked increase of extracellular glutamate in different areas, including the hippocampus, amygdala and prefrontal cortex of rats subjected to different stressors or to treatment with corticosterone (the main stress hormone in rodents; reviewed in [4,13]). It was also demonstrated, using different methodologies, that the rapid increase of extracellular glutamate levels is related to increased depolarization-evoked release, mediated by corticosterone membrane-located receptors (mineralocorticoid receptor in hippocampus, glucocorticoid in prefrontal and frontal cortex) coupled to nongenomic (protein synthesis-independent) mechanisms [14,15]. Chronic antidepressants nearly or completely abolish the stress-induced upregulation of glutamate release in cortical areas, suggesting that this drug effect may be a relevant component of the therapeutic action of antidepressants.…”

“…Moreover, the dampening action of chronic antidepressants on the stress-induced upregulation of glutamate release, observed in preclinical models [15], suggests a new putative line of drug development directly targeted at the molecular mechanisms regulating glutamate release [4,13]. In this context, a pharmacological modulation of presynaptic release of glutamate might provide a means of attenuating exaggerated or inadequate stress response in mood/anxiety disorders.…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…Learned helplessness in rats is a widely-used behavioral model of depression. The underlying mechanism is associated with a marked increase in depolarization-evoked glutamate release in the PFC, which can be mitigated by monoaminebased antidepressants [44][45][46] . Moreover, antidepressants reduce the release of glutamate, possibly by decreasing phospho-activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) [47] .…”