title: Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Pharmacological Sciences, Center of Neuropharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Musazzi
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Farisello
authors.forename: Simona
authors.initials: S
authors.lastname: Zappettini
authors.forename: Daniela
authors.initials: D
authors.lastname: Tardito
authors.forename: Valentina S
authors.initials: VS
authors.lastname: Barbiero
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bonifacino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mallei
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Raiteri
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003345:Corticosterone / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy*
chemical_list: D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D050600:SNARE Proteins; D018698:Glutamic Acid; D003345:Corticosterone