RGS2 mediates the anxiolytic effect of oxytocin

Abstract

The neuropeptide oxytocin (OT) has been shown to exert multiple functions in both males and females, and to play a key role in the regulation of emotionality in the central nervous system (CNS). OT has an anxiolytic effect in the CNS of rodents and humans. However, the molecular mechanisms of this effect are unclear. Here we show that OT induced the expression of regulator of G-protein signaling 2 (RGS2), a regulatory factor for anxiety, in the central amygdala (CeA) of female mice. Bath application of OT increased RGS2 levels in slices of the amygdala of virgin mice. RGS2 levels in the CeA were higher in lactating mice than in virgin mice. In contrast, RGS2 levels in mice that had given birth did not increase when the pups were removed. Acute restraint stress for 4h induced RGS2 expression within the CeA, and local administration of an OT receptor antagonist inhibited this expression. Behavioral experiments revealed that transient restraint stress had an anxiolytic effect in wild-type females, and RGS2 levels in the CeA correlated with the anxiolytic behavior. By contrast, in the OT receptor-deficient mice, restraint stress neither increased RGS2 levels in the CeA nor had an anxiolytic effect. These results suggest that OT displays an anxiolytic effect through the induction of RGS2 expression in the CNS.

Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice

“…Oxytocin treatment resulted in anxiolysis and was associated with increased RGS2 expression in mice (Okimoto et al . ).…”

Oxytocin: a therapeutic target for mental disorders

“…In rodents, direct hippocampal infusion of brain-derived neurotrophic factor (BDNF) has anxiolytic and antidepressant-like effects [41]. BDNF gene expression was also found to be up-regulated in primary cultured neurons treated with OT by microarray analysis [42]. In addition, stress and corticosterone strongly influence the phosphorylation of CREB in the hippocampus.…”

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

“…Multiple reports have shown a role for this RGS protein in modulating anxiety, with polymorphisms in RGS2 associated with generalized anxiety disorder (Smoller et al, 2008;Koenen et al, 2009;Hohoff et al, 2015), panic disorder Otowa et al, 2011;Hohoff et al, 2015), post-traumatic stress disorder , as well as suicide (Cui et al, 2008) in humans. Studies in mice have also shown an association between RGS2 and anxiety (Oliveira-Dos-Santos et al, 2000;Yalcin et al, 2004;Lifschytz et al, 2012;Okimoto et al, 2012) with decreased RGS2 expression causing anxiety (Oliveira-Dos-Santos et al, 2000;Lifschytz et al, 2012) and depression-like (Lifschytz et al, 2012) phenotypes. To better treat these diseases associated with RGS2, it is necessary to understand how RGS2 modulates synaptic plasticity and signaling.…”

“…Ga q at the RGS domain (Heximer et al, 1997;Ingi et al, 1998) Hippocampus (Han et al, 2006) Presynaptic in hippocampal pyramidal neurons (Han et al, 2006) Regulates short-term synaptic plasticity in the hippocampus (Han et al, 2006) Anxiety (Doupnik et al, 1997;Lifschytz et al, 2012;Okimoto et al, 2012;Hohoff et al, 2015) Ga i/o at the RGS domain (Ingi et al, 1998;Han et al, 2006) Striatum (Labouèbe et al, 2007) Postsynaptic in dopamine neurons in the VTA (Labouèbe et al, 2007) Disinhibits GABA-mediated inhibition of dopamine neurons in the VTA (Labouèbe et al, 2007) Depression (Lifschytz et al, 2012;Mandelli and Serretti, 2013) Amygdala (Okimoto et al, 2012) NA (Not available)…”

“…In the amygdala, RGS2 expression is induced upon administration of oxytocin (Okimoto et al, 2012), potentially mediating the anxiolytic effects of the neuropeptide. This may explain the relationship between anxiety and RGS2, although additional studies where RGS2 expression cannot be induced by oxytocin (RGS2-KO mice) must be performed to ensure that RGS2 is necessary to mediate oxytocin's anxiolytic effect.…”