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Rapid Central Corticosteroid Effects: Evidence for Membrane Glucocorticoid Receptors in the Brain1
Integrative and Comparative Biology, Sep 2005 by Tasker, Jeffrey G, Di, Shi, Malcher-Lopes, Renato
These findings point to a rapid corticosteroid action mediated by the activation of a membrane-associated receptor and a G protein/protein kinase-dependent mechanism (Fig. 4A), and corroborate the increasing body of evidence for non-transcriptional corticosteroid effects mediated by putative membrane glucocorticoid receptors. Interestingly, our findings indicate that the activation of these receptors in the PVN leads to the suppression of glutamatergic synaptic inputs to PVN parvocellular neuroendocrine cells via a novel mechanism involving the retrograde release of an endocannabinoid (Fig. 4B). Indeed, we have preliminary evidence from liquid chromatography-mass spectrometry analyses in brain slices indicating that dexamethasone elicits a significant increase in the levels of the endocannabinoids anandamide and 2-arachidonoylglycerol in the rat PVN and supraoptic nucleus, but not in the cerebellum (Malcher-Lopes et al., 2004), which corroborates our electrophysiological findings and supports our model of glucocorticoid suppression of excitatory synaptic inputs to PVN parvocellular neurons via the retrograde release of endocannabinoids (Fig. 4). Additionally, we have preliminary confocal immunohistochemistry data showing colocalization of CB1 cannabinoid receptors with the vesicular glutamate transporter 2, a marker of glutamate synaptic boutons, in the PVN (Di and Tasker, 2003), which suggests CB1 expression in presynaptic glutamatergic synaptic terminals in the PVN and provides further support for our model. Although, at this point, this model seems the most parsimonious for explaining the observed rapid effects of glucocorticoids on synaptic glutamate inputs to PVN neuroendocrine cells, we cannot yet exclude other alternative models that might also account for these observations, including the possibility of a glial cell intermediate and neuronal-glial interactions to stimulate endocannabinoid release.
These findings provide a likely mechanism for the rapid feedback inhibition of the HPA axis by glucocorticoids directly at the level of the hypothalamic CRH neurons. However, this effect was also seen in parvocellular neurons of the PVN that express TRH, oxytocin and vasopressin (Di et al., 2003), and in magnocellular neurons that express oxytocin and vasopressin (Di et al., 2005), indicating that the rapid glucocorticoid inhibition is not limited to the CRH neurons and the HPA axis, but also acts on other neuroendocrine systems, such as the hypothalamic-pituitary-thyroid and the hypothalamic-neurohypophysial axes. Although unexpected, this finding is not surprising considering the evidence for inhibitory effects of glucocorticoids on various neuroendocrine systems (Brabant et al., 1987; Papanek and Raff, 1994; Tsigos and Chrousos, 2002). It suggests that glucocorticoid-induced retrograde endocannabinoid release may be a more generalized mechanism by which stress levels of glucocorticoids exert a rapid inhibitory influence on neuroendocrine function. The fact that both glucocorticoids and endocannabinoids have well-established central orexigenic actions in the control of energy homeostasis (Kirkham et al., 2002; Zakrzewska et al., 1999), and that CRH, TRH, oxytocin and vasopressin have all been shown to regulate metabolic function and feeding behavior (Rondeel et al., 1992; Burlet et al., 1992; Verbalis et al., 1986), suggest that this mechanism may also play an important role in the neuroendocrine regulation and central coordination of stress and feeding.
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