Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: A fast feedback mechanism

Division of Neurobiology, Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118-5698, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2003; 23(12):4850-7.
Source: PubMed


Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic-pituitary-adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-beta-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist N(G)-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(beta)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcripton-PCR analysis, were subject to rapid inhibitory glucocorticoid regulation, including corticotropin-releasing hormone-, thyrotropin-releasing hormone-, vasopressin-, and oxytocin-expressing neurons. Therefore, our findings reveal a mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN and provide a link between the actions of glucocorticoids and cannabinoids in the hypothalamus that regulate stress and energy homeostasis.

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    • "Considering leptin inhibits hypothalamic endocannabinoid production, hypothalamic endocannabinoids are increased in genetically obese rodents lacking leptin and/or its receptor (Di Marzo et al., 2001). In thè PVN, glucocorticoidinduced suppression of glutamatergic inputs is mediated through retrograde release of endocannabinoids, an effect that is blocked by leptin (Di et al., 2003; Malcher-Lopes et al., 2006). Accordingly, leptin inhibition of glucocorticoidinduced , endocannabinoid-mediated suppression was absent in leptin receptordeficient obese Zucker rats (Malcher-Lopes et al., 2006). "

    Full-text · Chapter · Dec 2015
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    • "Furthermore, dehydrated animals show hyperosmolality-induced hypophagia to correct hyperosmolality (Watts and Boyle, 2010). ECF osmolality and volume changes also activate the hypothalamus– pituitary–adrenal axis (HPA), promoting glucocorticoid release (Lauand et al., 2007) that, in turn, inhibits OT and AVP release (Di et al., 2003Di et al., , 2005Di et al., , 2009Ruginsk et al., 2007Ruginsk et al., , 2010Ruginsk et al., , 2012) through retrograde messengers , such as nitric oxide, which stimulate the release of γ- aminobutyric acid (GABA) and lipid-derived mediators (endocannabinoids, ECBs), which inhibit the release of glutamate within the PVN and SON (Di et al., 2003Di et al., , 2005Di et al., , 2009). ECBs have been recognized as important signaling molecules that regulate energy homeostasis, not only by stimulating food intake and increasing body weight gain, but also by reducing energy consumption (Pagotto et al., 2006). "
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    • "Corticosteroids bind to two types of corticosteroid receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), which differ in their localization in the brain and affinity for corticosterone (Reul and de Kloet, 1985; de Kloet et al., 2005). Both MRs and GRs can exert slow genomic actions on cellular function, but recent studies have demonstrated that activation of these receptors can also activate fast membrane receptor mediated non-genomic pathways (Di et al., 2003; Karst et al., 2005, 2010; Groc et al., 2008; Groeneweg et al., 2011). "
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