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, Department of Psychology, University of Vermont, Burlington, VT, US Hammack, Sayamwong E., Department of Psychology, University of Vermont, Burlington, VT, US Falls, William A., Department of Psychology, University of Vermont, Burlington, VT, US, email@example.com Address: Falls, William A., Department of Psychology, University of Vermont, 2 Colchester Avenue, Burlington, VT, US, 05405, firstname.lastname@example.org Source: Behavioral Neuroscience, Vol 122(4), Aug, 2008. pp. 943-948 Publisher: US: American Psychological Association ISSN: 0735-7044 (Print) 1939-0084 (Electronic) Language: English Keywords: anxiety; serotonin; meta-chlorophenylpiperazine; wheel running; 5-HT2C receptor; mice; acoustic startle; exercise Abstract: Voluntary exercise has been associated with reduced anxiety across several animal models. Manipulation of central 5-HT can alter anxiety-like behaviors and administration of the 5-HT agonist metachlorophenylpiperazine (mCPP) increases anxiety in rodents and humans. To examine whether the anxiolytic effect of exercise is associated with an alteration in 5-HT systems, we examined the anxiogenic effect of mCPP in exercising and nonexercising mice. C57BL/6J mice were given 2 weeks of free access to either a functioning or nonfunctioning running wheel. Mice were then tested for acoustic startle following systemic injection of either 0, 0.1, 0.3, or 1 mg/kg of mCPP. Consistent with its anxiogenic properties, mCPP produced a dose-dependent increase in acoustic startle in nonexercising mice. However, this anxiogenic effect was blunted in exercising mice. These findings suggest that exercise may help to reduce anxiety by altering 5-HT systems, perhaps by down-regulating postsynaptic 5HT 2B/2C receptors. (PsycINFO Database Record (c) 2010 APA, all rights reserved) (from the journal abstract) Subjects: *Anxiety; *Exercise; *Piperazines; *Serotonin; *Serotonin Agonists; Auditory Stimulation; Mice; Neural Receptors; Startle Reflex Classification: Psychopharmacology (2580) Population: Animal (20) Male (30) Methodology:
First Submitted Date: Nov 30. Print Format Covered: Electronic Publication Type: Journal. 2.1037/0735-7044. Revised Date: Feb 8. 2007 Release Date: 20080825 Copyright: American Psychological Association. 8.943 PsycINFO AN: 2008-09788-023 Accession Number: bne-122-4-943 Number of Citations in Source: 93 Database: PsycARTICLES Translate Full Text: HTML Full Text Exercise Is Associated With Reduction in the Anxiogenic Effect of mCPP on Acoustic Startle Contents 1. 3. 9. Peer Reviewed Journal Document Type: Journal Article Publication History: Accepted Date: Feb 12.Empirical Study. 6. 2008. Method Subjects Drugs Apparatus Procedure Statistical Analysis Results Discussion References . Digital Object Identifier: 10. 5.4. Quantitative Study Format Availability: Electronic. 7. 2008.122. 4. 2008.
1999b. University of Vermont Sayamwong E. 2002. Reigle. Christie. & Greenough. 2001) and signaling molecules (Shen. increased expression of neurotrophins (Gomez-Pinilla. van Praag. Friedland et al. Trivedi. Alcantara. & Cotman. van Praag et al. Farmer et al. Fox Department of Psychology. 2001. Laurin. 2001. Smith. & Dishman. 1996. 2004b). exercise) benefits the cardiovascular system and thereby improves physical health. & Greenough. Anderson... & Helmstetter. 2005. capillary growth and increased vascular flow (Black. & Gage. Moraska & Fleshner. Dishman et al. Graham. 2001. Scully. 2002.. Chunm. voluntary exercise in rodents is associated with neurogenesis. Roy. Voluntary exercise in rodents has been shown to improve immunological and behavioral responses following stress (Dishman. 2001) and has been associated with improvements in attention (Hillman et al. & Fleshner. 2005. Meade. Greenwood et al. 2002.. 1992.. & Farrar. voluntary exercise in rodents improves learning and memory across several tasks and can mitigate cognitive decline in senescent mice (Baruch. 2005. Black. 2000). 2004. Fordyce & Wehner. 2005). Perreau.Download MP3 Help Listen By: James H. Fordyce.edu. & O'Neal. 1985. Consistent with these effects. Balazs. Laurin et al.. Hillman. 1996. Isaacs. 2001. 2001. 2000.. In humans. 1997. 1991. Verreault. 2005). Kremer. Maier. Ying. exercise has been associated with improvement in treatment outcomes for both depression and anxiety (Dunn. 2005. Falls. Youngstedt. Burhans. & Gage. Molteni. 2001. Balazs. Swain. Snook. Hammack Department of Psychology. van Praag et al. Gomez-Pinilla. & Gage. 2006. increased neuronal survival (Brown et al. Starnes.. Dunn et al. 2005. Morgan & Goldstein. Choi. Burlington. Manger & Motta. Tong. & Rockwood. Lindsay. 1991)... 2006). 1999b. Overton et al. In humans. 2004). and changes in serotonin (Greenwood.e. & Edgerton. Fleshner. Physical exercise also affects emotional health. 1999a. Kramer. 1993.. dementia and Alzheimer's disease (Friedland et al. & Gomez-Pinilla. 2 Colchester Avenue. 2001). Department of Psychology. 2003a). Armstrong.. Anderson. norepinephrine and Gamma-aminobutyric acid (GABA) (Dunn.. Falls Department of Psychology. 2002) and improves cognitive and emotional health (Dishman et al. Kempermann. 2003). University of Vermont William A. Christie et al. & McAuley. Shen. 2001. Fordyce & Farrar. Alcantara. changes in gene expression (Tong. Fox. & Cotman. Cotman & Engesser-Cesar. 1987. Although the exact mechanisms by which exercise benefits the brain are unclear (Cotman & Berchtold. 1998) and may be particularly effective in managing posttraumatic stress disorder (PTSD) (Manger & Motta.falls@uvm. 2003. Soares et . van Praag.. 1991. 1999a. 1999. Foley. Radak et al. Salmon.. van Praag. Vaynman. 2004. 2004a. MacPherson. 1995. Swain et al. physical exercise is associated with a lower risk of cognitive impairment. It is well known that physical activity (i. 1990.. Sejnowski.. 2005. Samorajski et al. Kennedy. University of Vermont Correspondence concerning this article should be addressed to: William A. Neeper. VT 05405 Electronic Mail may be sent to: william. 1996. & Cotman.. Belopolsky. Ying. & Dudgeon. University of Vermont. 2004. Isaacs. & Fleshner. There is now a growing evidence that exercise also benefits the brain (Cotman & Berchtold. 2000).
De Andrade.3 km. Ohl. Falls. 1996. 2003): drugs and environmental conditions known to increase anxiety increase acoustic startle (Grillon. Walker. Duffy.. The acoustic startle response is a sensitive measure of anxiety (Davis. Walker & Davis. 2005) that the total distance run in 24 hours per cage is 18. 2003. 1996. Following this. 1996). Cages of mice were randomly assigned to exercise or nonexercising groups.. C57BL/6J mice were given 2 weeks of voluntary access to a running wheel. & Szabados. Mice were housed in groups of four and maintained on a 12-h light/dark cycle (lights on at 0700 hours). & Sharp. and 1. However. it is likely that changes in central 5-HT functioning play some role in the anxiolytic effects of exercise (Greenwood et al. 2003b). & Guimaraes.. Mice were housed for 2 weeks with the running wheel before the beginning of experiments. Graeff. 1993. Metachlorophenylpiperazine (mCPP) is anxiogenic in humans (Feuchtl et al. then mice given access to a running wheel will show a blunted anxiogenic response to mCPP. Dunn et al. given the important role of serotonin (5-HT) in anxiety [see (Handley. mice were injected with mCPP (0. we tested whether exercise in mice would be associated with a decrease in the anxiogenic effect of mCPP. & Reul. 1996. BilkeiGorzo. 1997. Food and water were available ad libitum. 1997) whereas drugs and environmental conditions known to decrease anxiety decrease acoustic startle (Davis et al. Schmid. 0. We have previously shown (Detroy et al. Risbrough & Geyer. Any number of adaptive changes in the brain could contribute to the anxiolytic effect of voluntary exercise (Dishman et al. Maine). Pellowski. 1995) for review] and in the etiology and treatment of anxiety disorders.al.0 mg/kg. Consistent with this.. nonfunctioning running wheel. Method Subjects Male C57BL/6J mice (n = 59) were obtained from Jackson Laboratories (Bar Harbor. Schweimer. Del-Ben. 1997b. If exercise is associated with an alteration in 5-HT systems. 1996. 1999) and to produce a reduction in anxiety as measured in the open field (Dishman et al. Exercise groups were given free access to a functioning running wheel while nonexercising groups had access to a locked.. 2005). 1993.3. & Deakin. Soares et al.. 2005. Thompson & Rosen.. Lee & Davis.. 2005) and rodents (Abrams et al.. Toufexis. 2004).05 km (±0. ip) and tested for acoustic startle. 1996. we have recently shown that voluntary exercise in C57BL/6J mice produces a robust anxiolytic effect as evidenced by a reduction in startle amplitude. 2003. approximate average of 4. Cornelio & Nunes-de-Souza. Because exercise in rodents is anxiolytic and has been associated with alterations in central 5-HT functioning (Greenwood et al. 2004). elevated plus maze and the light-dark box (Binder. 1999). 0. Droste. 1997. This is consistent with published reports indicating that C57BL/6J given free access to a running wheel . & Falls. decreased stress-induced hyperthermia and increased social interaction (Detroy. Guignon.. Campeau. & Davis.1. Garcia-Leal. Gyertyan. & Schnitzler. & Davis. 2004. & Schnitzler. Graeff. Salchner. Fendt. 2005). Merikangas.5 km per mouse). 2005) and has been associated with activation of brain areas that are known to participate in the regulation of anxiety-related behaviors (Singewald. Gatch. 2007. increased time spent in the center of an open field. Koch. 2006). Guimaraes.. & Kim.
and 105 dB) presented in a pseudorandom order with the constraint that each startle intensity occur once in each block of three stimuli. 1999). The order of doses for each mouse was determined using a Latin Square design such that on each test day an equal number of mice received each dose. 0. The interval between successive doses of mCPP (i. The chamber was constructed of clear acrylic. 2005). and digitized over a range of 0 to 4.will run approximately 4 to 5 km in a 24-h period (Droste et al. This procedure was repeated three additional times until each mouse had been given each dose of mCPP. The intertrial interval was 60 seconds. weighed. VT).e. Mice were removed from their cage. with an inner diameter of 5 cm (Med Associates. 0. Doses of 0..5 cm in length.3 mg/kg and 1. Startle stimuli were 20 ms bursts of white noise (10 each at 95. between successive startle tests) was 48 hours. Data collection and the control and sequencing of all stimuli were controlled by Med-Associates startle reflex hardware and software (Georgia. Each cubicle was lined with black. . VT).1 mg/kg. Startle responses were transduced by the load cell. sound absorbing foam with no internal source of light. Injections were given 15 minutes before the test for acoustic startle (Risbrough & Geyer. Furthermore. 2003. a detailed video analysis of night cycle running in a sample of four cages revealed that each individual mouse runs on average 25% of the total time (range 17 and 38%). and injected with one of four doses of mCPP.0 mg/kg were administered intraperitoneal in a volume of 10 ml/kg. Harri et al... Each cubicle contained a stabilimeter device consisting of a load cell platform onto which the behavioral chamber was mounted. mice were placed in the startle apparatus. 100. Apparatus Acoustic startle was measured in eight individual sound attenuating cubicles measuring 58 (W) × 32 (D) × 55 (H) cm. amplified. Startle amplitude was defined as the largest peak to trough value within 100 ms after the onset of the startle stimulus. There are also no differences in body weight between exercising and nonexercising mice (Droste et al. and 1 mg/kg).096 units. Louis. Fifteen minutes later. St. cylindrical in shape. 12.. 2003. Georgia. 100. and 0. the mice were given the first of 30 noise burst startle stimuli (10 each at 95. 1999).1. Procedure The experiment was carried out with a within subjects design in which each mouse within an exercising group was given each of the four doses of mCPP (0.3. MO) was mixed fresh in physiological saline for each injection day.. Drugs mCPP HCl (Sigma-Aldrich. and 105 dB) provided through Radio Shack Supertweeters. Mice were transported to the lab from the colony in their home cage. 0. one located in each sound attenuating cubicles 10 cm behind each behavioral chamber. Harri et al. After a 5-min acclimation period during which no stimuli were administered.
0. 2001.g. 0. p < .0 mg/kg) in exercising mice (p < . Ciruli... p < .. 2004.. F(3. Alleva. Results As we have previously reported (Detroy et al. Hand. Because anxiolytic treatments decrease acoustic startle (Grillon et al. including differences in species (rat or mouse). Dishman et al.05. 1997). Although these inconsistencies may be because of any number of experimental variables. duration of exercise and anxiety model. Fox. 2004). F(1.. Morgan & Goldstein. 2005). 1. mCPP produced a dose dependent facilitation in startle in nonexercising mice F(3. no effects (Pietropaolo. & Wilson.1. nonfunctioning) running wheel (nonexercising group) (Figure 1.. single vs. we show that 2 weeks of voluntary exercise reduced acoustic startle amplitude and blunted the startle-enhancing effect of the anxiogenic drug mCPP. In studies allowing animals voluntary access to a running wheel there are reports of anxiolytic effects (Binder et al. 2001. nonexercising. 171) = 2.. Lee & Davis..9. in rodents the anxiolytic effects of exercise has been somewhat more variable. 1997). Schweimer et al.93. only the highest dose of mCPP facilitated startle in exercising mice. 171) = 2. The data were analyzed with a repeated measures analysis of variance (ANOVA) with group (exercising or nonexercising) and dose (0. sex. ANOVA revealed significant main effects of group (exercising vs. Discussion Several clinical studies have suggested an anxiolytic effect of regular exercise in humans (Dunn et al. However. 2005).e. 1987. Scully et al. only the highest dose of mCPP significantly facilitated startle (1. The significant interaction was followed up with lower order ANOVAs for each group.05). 1998).Statistical Analysis Mean startle amplitude was computed for each mouse at each dose.. 57) = 33.3. 1996.05. whereas anxiogenic treatments increase acoustic startle (Davis et al. mice given access to a running wheel (exercising group) exhibited lower acoustic startle amplitude than mice given access to a locked (i. 0 mg/kg mCPP).93. 1999. Fulk. 2006) or increases in anxiety-like behavior following exercise (Burghardt. In contrast. p < . 1997. mCPP dose dependently facilitated acoustic startle in nonexercising mice. housing conditions (e.05) and mCPP dose (F(3. 1996. 1997b. 1988). 2005. however. grouped housed). Each dose of mCPP elevated startle above the 0 mg/kg dose (Student-Newman–Keuls test..05). they point to the need for continued assessment of the putative anxiolytic effects of exercise in animal models. we interpret these data as being consistent with an anxiolytic effect of voluntary exercise. Post hoc analyses with Newman–Keuls paired t tests were used to test for differences within groups across the doses of mCPP (Hays.0 mg/kg) as independent factors and startle amplitude as the dependent factor. Manger & Motta. ps < . In this study. p < . this effect was blunted in exercising mice. The fact that 2 weeks of exercise was sufficient to produce an anxiolytic effect is interesting in light of the fact that studies typically allow rodents . Salmon. & Yee. Koch et al. 1993. In fact. Walker & Davis.05) as well as a significant dose by group interaction. 171) = 30. Feldon..
& Guezennec.. There is substantial . and without the benefit of highly selective antagonist studies examining the principal receptor subtypes responsible for augmenting acoustic startle. In their experiments. Legrand. Gomez-Merino. mCPP is a 5-HT agonist. in turn. 2001. 2001. Barnfield.. 2003). 1994. 2003.. Meeusen et al. Curzon & Kennett. Wood. Greenwood et al. Although mCPP has high affinity for 5-HT2C receptors. but not 3 days. This. 2003b). 2003a).. and because the cortisol response to mCPP is largely mediated by 5-HT2B/2C receptors (Broocks et al. Individuals completing a 10-week exercise regimen and subsequently challenged with an oral dose of mCPP showed a decreased cortisol response as compared to their response in a preexercise challenge (Broocks et al.. Consistent with this. frontal cortex. this suggests voluntary exercise exerts its anxiolytic effect in part through altering central 5-HT function (Greenwood et al. Bequet. Treadmill running appears to be qualitatively different from voluntary exercise and has been argued to be more akin to stress (Dunn et al. it is currently unknown whether mCPP enhances startle by actions at 5-HT2C receptors or another 5-HT receptor subtype. it is possible that exercise additionally affects postsynaptic 5-HT function. Kesslak. Berthelot. should decrease 5-HT release in DRN projection areas that are known to play a role in anxietyrelated behaviors. 2001). Shah. & Privat. mCPP is thought to mediate its anxiogenic effects through actions at the 5-HT2C receptor (Campbell & Merchant. 2001). Dishman and colleagues (Dishman et al. 1989. Gomez-Merino. 2005). it is interesting that treadmill running may also produce qualitatively different effect on the 5-HT system. additional 5-HT1A autoreceptors would decrease DRN activity by enhancing autoinhibition of DRN cell firing. Gerin. based on the present data. Gibson.. In humans. 1996). Kennett et al. In this light. 1990. we can only speculate the anxiolytic effect of exercise on acoustic startle is mediated by alterations in 5-HT2C receptors. Whitton. 1994. it also binds to several other 5-HT receptor subtypes (Hoyer et al. forced) exercise has been shown to increase 5-HT release in the hippocampus. Unpublished data from our lab suggests that 1 week. Chou. of exercise is sufficient to reduce startle amplitude and the reduction in startle amplitude persists as long as the mice are allowed to run (up to 12 weeks). Chinn. & Curzon. Kennett. It is interesting to note that treadmill (i. If the up-regulation of mRNA for 5-HT1A somatodentritic autoreceptors results in an up-regulation of receptor protein. 1996). 1997) have reported that voluntary exercise in rats was associated with decreased shock-induced elevation in the 5-HT metabolite 5-hydroxyindole acetic acid in the hippocampus and amygdala suggesting that exercise decreased 5-HT function in these DRN targets associated with anxiety-like behavior. 1999). Berthelot. (2003) have provided further evidence that voluntary exercise alters central 5HT function. Clearly much more work is needed examining how the duration of exercise influences the reduction in anxiety (see Berchtold... 1996. & Cotman.. and because voluntary exercise was associated with a blunted effect of mCPP. and spinal cord (Bequet.e. 2002. Chennaoui. Porter et al. 6 weeks of voluntary exercise in rats was associated with an up-regulation of mRNA for 5-HT1A somatodentritic autoreceptors in the dorsal raphe nucleus (DRN) (Greenwood et al. 1994. 2005.. exercise has also been shown to blunt the effect of mCPP. In addition to the documented exercise-induced changes in presynaptic 5-HT function.to run for up to 6 weeks. Therefore. & Guezennec. Therefore.. With this. & Curzon. Broocks and colleagues hypothesize that exercise leads to a down-regulation of central 5-HT2B/2C receptors.
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