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.


Available from: Jeffrey Tasker
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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). "

    Cannabinoids in Neurologic and Mental Disease, 12/2015: pages 389-413; , ISBN: 9780124170414
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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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    ABSTRACT: Mineralocorticoid receptors (MRs) have been implicated in behavioral adaptation and learning and memory. Since-at least in humans-MR function seems to be sex-dependent, we examined the behavioral relevance of MR in female mice exhibiting transgenic MR overexpression in the forebrain. Transgenic MR overexpression did not affect contextual fear memory or cued fear learning and memory. Moreover, MR overexpressing and control mice discriminated equally well between fear responses in a combined cue and context fear conditioning paradigm. Also context-memory in an object recognition task was unaffected in MR overexpressing mice. We conclude that MR overexpression in female animals does not affect fear conditioned responses and object recognition memory.
    Frontiers in Behavioral Neuroscience 07/2015; 9:182. DOI:10.3389/fnbeh.2015.00182 · 3.27 Impact Factor
    • "The HPA axis response to restraint is rapidly inhibited by glucocorticoids through an endocannabinoid-mediated signaling pathway, on a similar time scale to that reported in the current manuscript [17] [22]. Because of this similarity in time course, and because mGluR type I receptors in many cases mediate endocannabinoid signaling [11] [10], we hypothesized that metabotropic glutamate receptors may be part of the signal cascade that mediates the fast inhibitory effects of glucocorticoids on the HPA axis [23]. "
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    ABSTRACT: Glutamate is an important neurotransmitter in regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 02/2015; 61. DOI:10.1016/j.physbeh.2015.02.027 · 2.98 Impact Factor
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