TY - JOUR T1 - Glucocorticoids Regulate Glutamate and GABA Synapse-Specific Retrograde Transmission via Divergent Nongenomic Signaling Pathways JF - The Journal of Neuroscience JO - J. Neurosci. SP - 393 LP - 401 DO - 10.1523/JNEUROSCI.4546-08.2009 VL - 29 IS - 2 AU - Shi Di AU - Marc M. Maxson AU - Alier Franco AU - Jeffrey G. Tasker Y1 - 2009/01/14 UR - http://www.jneurosci.org/content/29/2/393.abstract N2 - Glucocorticoids exert an opposing rapid regulation of glutamate and GABA synaptic inputs to hypothalamic magnocellular neurons via the activation of postsynaptic membrane-associated receptors and the release of retrograde messengers. Glucocorticoids suppress synaptic glutamate release via the retrograde release of endocannabinoids and facilitate synaptic GABA release via an unknown retrograde messenger. Here, we show that the glucocorticoid facilitation of GABA inputs is due to the retrograde release of neuronal nitric oxide and that glucocorticoid-induced endocannabinoid synthesis and nitric oxide synthesis are mediated by divergent G-protein signaling mechanisms. While the glucocorticoid-induced, endocannabinoid-mediated suppression of glutamate release is dependent on activation of the Gαs G-protein subunit and cAMP–cAMP-dependent protein kinase activation, the nitric oxide facilitation of GABA release is mediated by Gβγ signaling that leads to activation of neuronal nitric oxide synthase. Our findings indicate, therefore, that glucocorticoids exert opposing rapid actions on glutamate and GABA release by activating divergent G-protein signaling pathways that trigger the synthesis of, and glutamate and GABA synapse-specific retrograde actions of, endocannabinoids and nitric oxide, respectively. The simultaneous rapid stimulation of nitric oxide and endocannabinoid synthesis by glucocorticoids has important implications for the impact of stress on the brain as well as on neural-immune interactions in the hypothalamus. ER -