Research Report RGS2 mediates the anxiolytic effect of oxytocin Naoki Okimoto a, b , Oliver J. Bosch c , David A. Slattery c , Konstanze Pflaum c , Hiroaki Matsushita a , Fan-Yan Wei d , Masayasu Ohmori a , Tei-ichi Nishiki a , Iori Ohmori a , Yuji Hiramatsu b , Hideki Matsui a , Inga D. Neumann c , Kazuhito Tomizawa d, ⁎ a Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700–8558, Japan b Department of Obstetrics & Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700–8558, Japan c Department of Neurobiology and Animal Physiology, University of Regensburg, Regensburg 93040, Germany d Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860–8556, Japan ARTICLE INFO ABSTRACT Article history: Accepted 4 March 2012 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 4 h 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. © 2012 Elsevier B.V. All rights reserved. Keywords: Anxiety Stress Amygdala Female Mouse 1. Introduction OT is the classical reproductive hormone in female mammals, promoting uterine contractions during labor and milk ejection during lactation (Gainer and Wray, 1994; Neumann, 2001). OT also acts as a neurotransmitter/neuromodulator to regulate a range of central nervous system functions in both males and females, including emotional (Neumann, 2008), parental (Numan and Insel, 2003), affiliative (Insel and Shapiro, 1992), and sexual (Argiolas and Gessa, 1991) behaviors, as well as spa- tial and social cognition (Bielsky and Young, 2004; Tomizawa et al., 2003). Moreover, OT is an important regulator of anxiety (Bale et al., 2001; Blume et al., 2008; Neumann et al., 2000a) and of stress-coping circuitries (Ebner et al., 2005; Huber et al., 2005). For instance, OT released in the hypothalamus mediates mating-induced anxiolysis in rats (Waldherr and Neumann, 2007). Psycho-social or physical stressors like forced swimming and restraint stress evoke the release of OT in various areas BRAIN RESEARCH XX (2012) XXX – XXX ⁎ Corresponding author at: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto 860–8556, Japan. Fax: +81 96 373 5052. E-mail address: tomikt@kumamoto-u.ac.jp (K. Tomizawa). BRES-42171; No. of pages: 8; 4C: 0006-8993/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2012.03.012 Available online at www.sciencedirect.com www.elsevier.com/locate/brainres Please cite this article as: Okimoto, N., et al., RGS2 mediates the anxiolytic effect of oxytocin, Brain Res. (2012), doi:10.1016/ j.brainres.2012.03.012