title: Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.
abstract: The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.
authors.affiliation: Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA. malcherlopes@gmail.com
authors.forename: Renato
authors.initials: R
authors.lastname: Malcher-Lopes
authors.forename: Shi
authors.initials: S
authors.lastname: Di
authors.forename: Victor S
authors.initials: VS
authors.lastname: Marcheselli
authors.forename: Feng-Ju
authors.initials: FJ
authors.lastname: Weng
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Stuart
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Tasker
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D005989:Glycerides / Q000378:metabolism; D066298:In Vitro Techniques; D020738:Leptin / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D005989:Glycerides; D020738:Leptin; D003907:Dexamethasone; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP