Noradrenergic activity regulated dexamethasone-induced increase of 5-HT3 receptor-mediated glutamate release in the rat's prelimbic cortex

Stress hormone, glutamatergic system, serotonergic system and the noradrenergic system are involved in depressive disorders. However, the relationship among these is still unclear. The present study examined the effect of dexamethasone (DEX) on the presynaptic glutamate release of synaptosomes from the rat's prelimbic cortex by using biochemical methods combined with pharmacological approaches. The results showed that dexamethasone increased the glutamate release of synaptosomes in a dose-dependent manner. The concentration–response relationship of this effect of DEX was inverse U-shaped with a maximum at 3 μm. Further study showed that glucocorticoid receptor (GR) antagonist and GR siRNA had no effect on the DEX-induced glutamate release but 5-HT3 receptor antagonist could block the DEX-induced glutamate release which suggested that DEX produced the increased effect on the glutamate release not by GR, but through the activation of the 5-HT3 receptors which led to the influx of extrasynaptosomal Ca2 +. Moreover, β3 adrenergic receptor agonist could block the DEX-induced glutamate release. This result suggested that the effect of DEX on the glutamate release could be regulated by noradrenergic system. The mechanism study showed that β3 adrenergic receptors regulated the DEX-induced glutamate release via Gs protein–adenylate cyclase (AC)–protein kinase A (PKA) signal transduction pathway.

► DEX increased the glutamate release of synaptosomes in a dose-dependent manner. ► DEX exerts its effect not by GR, but through the activation of the 5-HT3 receptors. ► The activation of β3R inhibits the DEX-induced glutamate release by Gs–AC–PKA pathway.