Abstract
BackgroundGrowing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels.ResultsChronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes.ConclusionsOur data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
Highlights
Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders
We have shown that acute footshock-stress induces a marked increase of depolarization-evoked overflow of glutamate from prefrontal and frontal cortex synaptosomes, via glucocorticoid receptor activation and soluble N-ethylmaleimidesensitive fusion protein attachment protein receptor (SNARE) complex accumulation in synaptic membranes
Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked release of glutamate from hippocampal synaptosomes Synaptosomes were purified from the hippocampus of chronically drug- or vehicle-treated rats, and exposed in superfusion to KCl or ionomycin to assess glutamate and γ-amminobutyric acid (GABA) release
Summary
Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Results: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. We have previously found that chronic treatment with different antidepressants (fluoxetine, desipramine, reboxetine) significantly reduced depolarization-evoked glutamate release from hippocampal synaptic terminals (synaptosomes) [11]. We have shown that acute footshock-stress induces a marked increase of depolarization-evoked overflow of glutamate from prefrontal and frontal cortex synaptosomes, via glucocorticoid receptor activation and SNARE complex accumulation in synaptic membranes. Aims of the present work were: (1) To assess whether chronic treatment with agomelatine modulates glutamate release from superfused hippocampal synaptosomes. (2) To study whether agomelatine reduces the accumulation of the presynaptic SNARE complex in hippocampus
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