Chronic cold exposure increases RGS7 expression and decreases α₂‐autoreceptor‐mediated inhibition of noradrenergic locus coeruleus neurons

Abstract

Chronic stress exposure alters the central noradrenergic neurons originating from the locus coeruleus (LC). Previously, we demonstrated that evoked increases in the firing rate of LC neurons and their release of norepinephrine are enhanced following chronic cold exposure. In the present studies, we tested the hypothesis that reduced feedback inhibition of LC neurons might underlie these alterations in LC activity by examining the effect of alpha(2)-autoreceptor stimulation on LC activity in chronically stressed rats using in vivo and in vitro single unit recordings. Given that regulators of G-protein signaling (RGS) proteins can impact the coupling of alpha(2)-autoreceptors to downstream signaling cascades, we also explored the expression of several RGS proteins following chronic stress exposure. We observed that the alpha(2)-autoreceptor-evoked inhibition of LC neurons was reduced and that the expression of RGS7 was increased following chronic stress exposure. Finally, we demonstrated that intracellular administration of RGS7 via patch clamp electrodes mimicked the stress-induced decrease in clonidine-evoked autoreceptor-mediated inhibition. These novel data provide a mechanism to explain how chronic stress-induced alterations in receptor coupling can result in changes in alpha(2)-autoreceptor control of noradrenergic function throughout the central nervous system, potentially leading to alterations in anxiety-related behaviors, and may suggest novel therapeutic targets for the treatment of mood and anxiety disorders.

Chapter 6 Structure, Function, and Localization of Gβ5–RGS Complexes

“…Another recent study also showed that RGS7 was upregulated when animals were stressed by chronic exposure to cold. 132 The detected increase of the RGS7 signal on the immunoblot was only about 20%, but was appreciable particularly because RGS4 and RGS2 levels did not change in the same preparations. Noteworthy, there was no corresponding increase in Gβ5 levels, although the reason for this is unclear.…”

“…133 The recent study of Jedema and colleagues indicates that the elevation of RGS7 attenuates signal transduction via the α2-adrenergic receptors in rat locus coeruleus, the area of the brain involved in stress. 132 These presynaptic Gi-coupled receptors provide negative feedback to the process of norepinephrine release. In this model, upregulation of RGS7 under conditions of chronic stress attenuates signaling via the α2-adrenegic receptors by accelerating the GTPase activity of Gi, which would result in a restoration of the system's ability to respond to subsequent stimuli.…”

“…127,132 Can small changes in the Gβ5–R7 level result in a physiologically meaningful effect on signal transduction? One idea to consider is that a stimulus causing upregulation of R7 could result in the generation of a small excess of the R7 subunit over Gβ5.…”

Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons

“…72,73 Chronic stress also downregulates 5-HT 1A autoreceptors within the DRN. 74,75 It is not known how long such adaptations may persist after recovery but our findings are nevertheless consistent with the putative role of stress in the physiopathology of addiction.…”

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

“…However, RGS7 is likely acting through a signaling cascade that is separate from the 5-HT 1A R-AC axis as it did not appear to play a compensatory role in the absence of RGS6 (22), and RGS7 was not able to modulate 5-HT 1A receptor signaling in vitro (65). In addition, RGS7 is also upregulated in the locus coeruleus (LC) of the mouse following chronic stress induced by cold exposure and is responsible for modulating the ability of the α 2 -autoreceptor to inhibit neuronal firing and release of norepinephrine (66). Finally, there is evidence suggesting that RGS9 may play a modulatory role in anxiety as RGS9-2 expression is upregulated in the NAc in response to a mouse model neuropathic pain.…”