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 G␣ s -cAMPprotein 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.

RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

“…Preclinical work suggests that the activation of membrane glucocorticoid receptors appears to engage a G-protein-mediated cascade through the activation of G s proteins (Di et al, 2003) that, in turn, increases the activity of cAMP and protein kinase A. This increase in protein kinase A appears to induce the rapid synthesis of an endocannabinoid signal through an as yet unknown mechanism that may be an increase in intracellular calcium signaling (Cadas et al, 1996;Malcher-Lopes et al, 2006;Vellani et al, 2008) that is then released from principal neurons in the amygdala and activates CB 1 receptors localized on the terminals of GABAergic neurons in the amygdala. It should be noted, however, that other mechanisms than CB 1 receptor stimulation by anandamide could contribute to the etiology of attentional bias to threat and threat symptomatology.…”

The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation

“…Indeed, such a mechanism has been shown to be responsible for (1) the disinhibition of the release of the orexigenic neuropeptide, a melanin-concentrating hormone (MCH), from LH neurons through a retrograde inhibition of g-aminobutyric acid (GABA) release; 9 and (2) the inhibition of anorectic neurons in the PVN after a sequential activation of either ghrelin or 'fast' glucocorticoid receptors in these neurons (which likely produce the corticotropin-releasing hormone (CRH)), the biosynthesis and release of ECs, and subsequent retrograde CB 1 -mediated inhibition of glutamate release from parvocellular neurons innervating these neurons. 10,11 In some cases, 9,10 these retrograde orexigenic actions of ECs are under the negative control of post-synaptic leptin receptors that reduce EC biosynthesis by decreasing intracellular calcium. In fact, it had been shown earlier that hypothalamic EC levels are inhibited by an intravenous injection of leptin in rats, an effect that is likely responsible for the permanently elevated EC levels in the hypothalamus of obese rodents that lack leptin (ob/ob mice) or fully functional leptin receptors (db/db mice and fa/fa Zucker rats).…”

The effects of two highly selective dopamine D3 receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity

“…These rats also exhibit hyperphagia, hypertriglycemia, and hyperinsulinemia (Boulange et al, 1979). Their genotype (fa/fa) denotes that they are homozygous for defective leptin receptors, which prevents leptin signaling in these animals (Malcher-Lopes et al, 2006). It has previously been shown that anorectic concentrations of leptin in the brain reduces the firing of mesolimbic DAergic neurons in vivo and suppresses DA-related motivational aspects of feeding (Krugel et al, 2003) which may indicate decreased DA levels in leptin receptor deficient obese Zucker (fa/fa) rats as one of the causes for obesity (Brunetti et al, 1999).…”