5-HT2C Receptors in the Basolateral Amygdala and Dorsal Striatum Are a Novel Target for the Anxiolytic and Antidepressant Effects of Exercise Benjamin N. Greenwood1,3*, Paul V. Strong1,3, Alice B. Loughridge1, Heidi E. W. Day2,3, Peter J. Clark1,3, Agnieszka Mika1,3, Justin E. Hellwinkel1, Katie G. Spence1, Monika Fleshner1,3 1 Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States of America, 2 Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America, 3 The Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America Abstract Physical activity reduces the incidence and severity of psychiatric disorders such as anxiety and depression. Similarly, voluntary wheel running produces anxiolytic- and antidepressant-like effects in rodent models. The specific neurobiological mechanisms underlying the beneficial properties of exercise, however, remain unclear. One relevant pharmacological target in the treatment of psychiatric disorders is the 5-HT2C receptor (5-HT2CR). Consistent with data demonstrating the anxiogenic consequences of 5-HT2CR activation in humans and rodents, we have previously reported that site-specific administration of the selective 5-HT2CR agonist CP-809101 in the lateral/basolateral amygdala (BLA) increases shock-elicited fear while administration of CP-809101 in the dorsal striatum (DS) interferes with shuttle box escape learning. These findings suggest that activation of 5-HT2CR in discrete brain regions contributes to specific anxiety- and depression-like behaviors and may indicate potential brain sites involved in the anxiolytic and antidepressant effects of exercise. The current studies tested the hypothesis that voluntary wheel running reduces the behavioral consequences of 5-HT2CR activation in the BLA and DS, specifically enhanced shock-elicited fear and interference with shuttle box escape learning. After 6 weeks of voluntary wheel running or sedentary conditions, the selective 5-HT2CR agonist CP-809101 was microinjected into either the BLA or the DS of adult Fischer 344 rats, and shock-elicited fear and shuttle box escape learning was assessed. Additionally, in-situ hybridization was used to determine if 6 weeks of voluntary exercise changed levels of 5-HT2CR mRNA. We found that voluntary wheel running reduced the behavioral effects of CP-809101 and reduced levels of 5-HT2CR mRNA in both the BLA and the DS. The current data indicate that expression of 5-HT2CR mRNA in discrete brain sites is sensitive to physical activity status of the organism, and implicates the 5-HT2CR as a target for the beneficial effects of physical activity on mental health. Citation: Greenwood BN, Strong PV, Loughridge AB, Day HEW, Clark PJ, et al. (2012) 5-HT2C Receptors in the Basolateral Amygdala and Dorsal Striatum Are a Novel Target for the Anxiolytic and Antidepressant Effects of Exercise. PLoS ONE 7(9): e46118. doi:10.1371/journal.pone.0046118 Editor: Masabumi Minami, Hokkaido University, Japan Received February 29, 2012; Accepted August 28, 2012; Published September 25, 2012 Copyright: 2012 Greenwood et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work in this manuscript was supported by the National Institutes of Health grant: NIMH 068283 (M.F.), NIMH 050479 (B.G.) and the American Foundation for Suicide Prevention (B.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ben.greenwood@colorado.edu Introduction Physical activity is associated with a reduction in the incidence and severity of psychiatric disorders such as anxiety and depression [1,2,3,4]. Similarly, voluntary exercise can reduce anxiety- [5,6,7,8,9,10,11] and depression- [8,12,13] like behaviors in laboratory rodents. Despite identification of many neuroadaptive changes produced by exercise [14,15,16], the specific neurobio- logical mechanisms underlying the anxiolytic and antidepressant properties of physical activity are unclear. Identification of these mechanisms could support the use of exercise as a prophylactic and therapeutic intervention for anxiety and depression, as well as provide insight into novel treatment strategies for psychiatric illness. Serotonin (5-HT) has long been implicated in anxiety [17,18,19,20,21] and depression [22,23], but the mechanisms by which 5-HT contributes to specific symptomatology of these disorders remain an intense topic of investigation. Emerging evidence points to a role for the 5-HT2C receptor (5-HT2CR) in the expression of specific symptoms of anxiety [24,25,26] and depression [27,28,29]. Extending prior reports of anxiogenic effects of 5-HT2CR agonists in humans [30,31,32,33,34,35,36,37] and rodents [38,39,40,41,42,43,44], our group has contributed to the identification of the specific brain regions that subserve specific behavioral effects of 5-HT2CR activation. Anxiety-like behavior, including exaggerated shock-elicited fear [45] and social avoidance [38,41], can be elicited in rats by site-specific activation of 5- HT2CR in the region of the lateral/basolateral amygdala (BLA), a brain area classically implicated in fear and anxiety [46,47]. In contrast, activation of 5-HT2CR in the dorsal striatum (DS) has no effect on anxiety behaviors, but can interfere with learning to escape in a shuttle box escape task, a common screening tool for antidepressant compounds [48]. Thus, 5-HT2CR activation in discrete brain regions appears to be a sufficient stimulus to elicit specific symptoms of anxiety- and depression-like behavior. PLOS ONE | www.plosone.org 1 September 2012 | Volume 7 | Issue 9 | e46118