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The Journal of Neuroscience, June 14, 2006, 26(24):6643-6650; doi:10.1523/JNEUROSCI.5126-05.2006

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Cellular/Molecular
Opposing Crosstalk between Leptin and Glucocorticoids Rapidly Modulates Synaptic Excitation via Endocannabinoid Release

Renato Malcher-Lopes,¹ Shi Di,² Victor S. Marcheselli,⁴ Feng-Ju Weng,² Christopher T. Stuart,³ Nicolas G. Bazan,⁴ and Jeffrey G. Tasker^1,2,3

¹Neuroscience Program, ²Neurobiology Division of the Cell and Molecular Biology Department, and ³Molecular Neurobiology Core Laboratory, Tulane University, New Orleans, Louisiana 70118, and ⁴Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Correspondence should be addressed to Renato Malcher-Lopes at his present address: Neural Microcircuitry Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Email: malcherlopes{at}gmail.com

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 CB₁ 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 G_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.

Key words: leptin; glucocorticoids; endocannabinoids; neuroendocrine; stress; energy homeostasis

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Received Dec. 2, 2005; revised April 15, 2006; accepted May 10, 2006.

Correspondence should be addressed to Renato Malcher-Lopes at his present address: Neural Microcircuitry Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Email: malcherlopes{at}gmail.com

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