Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons.
Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the brain to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion. Here we show using whole-cell patch clamp recordings that glucocorticoids elicit a rapid, opposing action on synaptic glutamate and gamma-aminobutyric acid (GABA) release onto magnocellular neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus, suppressing glutamate release and facilitating GABA release by activating a putative membrane receptor. The glucocorticoid effect on both glutamate and GABA release was blocked by inhibiting postsynaptic G protein activity, suggesting a dependence on postsynaptic G protein signaling and the involvement of a retrograde messenger. Biochemical analysis of hypothalamic slices treated with dexamethasone revealed a glucocorticoid-induced rapid increase in the levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The glucocorticoid suppression of glutamate release was blocked by the type I cannabinoid receptor cannabinoid receptor antagonist, AM251, and was mimicked and occluded by AEA and 2-AG, suggesting it was mediated by retrograde endocannabinoid release. The glucocorticoid facilitation of GABA release was also blocked by AM251 but was not mimicked by AEA, 2-AG, or a synthetic cannabinoid, WIN 55,212-2, nor was it blocked by vanilloid or ionotropic glutamate receptor antagonists, suggesting that it was mediated by a retrograde messenger acting at an AM251-sensitive, noncannabinoid/nonvanilloid receptor at presynaptic GABA terminals. The combined, opposing actions of glucocorticoids mediate a rapid inhibition of the magnocellular neuroendocrine cells, which in turn should mediate rapid feedback inhibition of the secretion of oxytocin and vasopressin by glucocorticoids during stress activation of the hypothalamic-pituitary-adrenal axis.
Division of Neurobiology, Tulane University, New Orleans, Louisiana 70118-5698, USA.
Shi
S
Di
Renato
R
Malcher-Lopes
Victor L
VL
Marcheselli
Nicolas G
NG
Bazan
Jeffrey G
JG
Tasker
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002784:Cholesterol / Q000494:pharmacology*; D003345:Corticosterone / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003907:Dexamethasone; D002784:Cholesterol; D003345:Corticosterone