Introduction
Rodent models have long been instrumental in uncovering the complex physiological and psychological processes driving human disease. However, our understanding of non-invasive and non-pharmacological interventions—those long deemed “alternative”—are sorely lacking. Voluntary wheel-running behavior in rodents serves as a valuable lens through which to explore the critical role of physical activity (PA) as a cornerstone of human health. Moreover, there is growing interest and clear need to investigate the mechanisms underlying traditional treatment options, like acupuncture. The complimentary contributions of this special topic investigate the interplay between everyday health factors—namely stress, PA levels, high-fat diet, and alcohol use—and the unique opportunity to implement adjunctive, non-invasive interventions to improve health.
Investigating neural and behavioral barriers to PA
Growing evidence suggests that adverse life experiences can negatively impact long-term PA levels (Moraska and Fleshner, 2001; Stults-Kolehmainen and Sinha, 2014; DeVallance et al., 2017; Chauntry et al., 2022; Raney et al., 2022). Yet, the biological factors mediating the connection between stress and PA motivation remain unclear. The contributed work of Buhr et al. presents several novel findings that may help elucidate this complex relationship. Here, wheel running was found to be inversely proportional to the number of tail shocks received, indicating a negative relationship between stress intensity and PA engagement. Similarly, stress exposure reduced the latency to reach failure on a graded treadmill test—a reliable measure of reduced PA performance, which may reflect features of low PA motivation. Follow-up testing found that tail-shock blunted PA-induced reductions in dopamine (DA) and serotonin (5HT) processing that were consistent across several brain regions. These findings reflect known adaptive stress-coping mechanisms in response to PA, which warrant further testing as potential neurobiological barriers to PA engagement (Dishman et al., 1997; Greenwood and Fleshner, 2011; Mul et al., 2018). Burh et al. also found that stress exposure increased HSP70 and decreased SOD2 protein concentrations in skeletal muscle—markers of prolonged oxidative stress and inflammation—that were otherwise unaltered by PA. Taken together, Buhr et al. provide critical insights into behavioral, central, and peripheral responses to adverse experiences that may mediate long-term PA deficits.
Despite known benefits of regular exercise, physical inactivity remains a global issue (Ruegsegger and Booth, 2018; Katzmarzyk, 2023). To address the insufficient biological understanding of exercise adherence, it may be important to consider the physiological stress of PA itself as a potential motivational barrier. Forced models of PA rodents, such as treadmill running, are largely considered more physiologically stressful than voluntary models (i.e., wheel-running). However, consistence evidence suggests that acute WR (1–2 weeks) evokes physiological and neurobiological markers of stress, whereas more chronic stages of voluntary PA (4-weeks) do not (Fediuc et al., 2006; Grigsby et al., 2022). In their contribution, Grigsby et al. introduced the 3D-printable, “Dependable, Simple, and Cost-effective (DSC)” running wheel as an affordable and precise means of exploring distinct running characteristics at key stages of PA reinforcement (Grigsby et al.); wherein wheel-running patterns at acute and chronic timepoints were characterized in a mouse model of harmful ethanol drinking (inbred High Drinking in the Dark; iHDID-1) and their heterogenous founders (Heterogenous Stock/Northport; HS/Npt). For both genotypes, there was a consistent increase in the average running distance from day 1 to day 14 of wheel access, which was maintained until day 28. This mirrors foundational wheel studies in mice and rats, which similarly show a shift toward habitual running patterns over time. In support of prior work (McCulley et al., 2013), iHDID-1 displayed less fluctuation in their 24-h running pattern compared to HS/Npt mice. Additional running characteristics, such as daily running distance, running time, and circadian actograms, were otherwise the same between both genotypes (and across both sexes; Grigsby et al.). In all, Grigsby et al. showcase the DSC wheel as a customizable, precise, and cost-effective tool for exploring PA behavior in real-time.
Sex-specific differences in PA and diet
Human disease is complex and often undifferentiating—studying both sexes is a clear and basic first step toward finding inclusive and effective medical treatments. Sex differences in rodent and human PA depend on genetic background, age, and environmental influences. Female rodents tend to run greater distances and at higher intensities than males; however, some mouse strains (i.e., CBA/J and CAST/Ei) show comparable running patterns between sexes (Lightfoot et al., 2004; Ghosh et al., 2010). The present contribution from Grigsby et al. also found little sex differences in wheel activity in iHDID-1 and HS/Npt mice. Despite their well-known strain difference in binge-like ethanol intake, few sex-specific differences in ethanol-related measures across iHDID-1 and HS/Npt mice have been noted (Crabbe et al., 2014; Jensen et al., 2021; Savarese et al., 2021). Expanding our understanding of the role of sex in PA and other patterned behaviors, such as substance use and high-fat feeding, is crucial for effectively guiding PA as an adjunctive therapy in the future.
The work provided by Kocum et al. investigated the effects of voluntary PA on diet preference between a palatable high-fat diet and a less palatable, nutritionally balanced diet in male and female Sprague-Dawley rats (Kocum et al.). Wheel access differentially shifted diet preference and consumption based on sex, wherein sedentary females consumed 20% less high-fat diet compared to their PA counterparts—indicative of an adaptive response to sedentary behavior. In contrast, males displayed a maladaptive, 50% increase in high-fat diet consumption under sedentary conditions. In both sexes, the effects of PA on diet preference were reversible within 24 h of alternating wheel conditions. Intriguingly, no correlation was found between running distance and diet intake, suggesting wheel access alone (not PA, per se) may influence feeding behavior. Kocum et al. further described sex-specific differences in striatal opioid and dopamine-related genes in response to PA and diet, with males showing increased expression of Drd2 and Penk and females showing decreased expression of Drd2, Opmr1, and Penk. These largely opposite gene responses may in-turn underscore sex-differences in sensitivity to the reinforcing properties of palatable food and PA. Taken together, this critical work underscores the complicated interplay between sex, sedentary behavior, and overconsumption of palatable foods.
Exploring adjunctive therapies in the context of alcohol use disorder
There are only three pharmacotherapies for U.S. citizens struggling with Alcohol Use Disorder (AUD). For some, these options are ineffective, cost prohibitive, or harbor side effects. Finding adjunctive, non-invasive treatment options that can complement existing therapies will undoubtedly act to offset these major downsides.
Voluntary ethanol intake and voluntary wheel-running have been widely studied since the early 20th century (Stewart, 1898; Hausmann, 1932). Furthermore, the relationship between PA and harmful drinking has been explored across species, strains, and in both sexes (Ozburn et al., 2008; Ehringer et al., 2009; Booher et al., 2019; Buhr et al., 2021). Although not directly addressed by Grigsby et al., future exploration of how these behaviors interact (in real-time) in iHDID mice could help better understand the potential of PA to regulate harmful drinking.
Acupuncture—which has been practiced in China since 2500 BC—has been explored as a potential treatment option for substance use disorders for decades (McLellan et al., 1993; Tan et al., 2025). For instance, implementation of a protocol developed by the US National Acupuncture Detoxification Association (NADA) has been shown to be effective in treating cocaine and opiate misuse in humans (Bullock et al., 1999; Lin et al., 2012). Acupuncture has similarly emerged as a potential intervention for alcohol dependence and related symptomology (Zhao et al., 2014; Chang et al., 2019). The contributed work of Seo et al. explored the effects of stimulating the HT7 (Shenmen) acupuncture point (in an anatomically analogous location) on ethanol intake in rats. Moreover, Seo et al. further examined microglia-related responses across the medial prefrontal cortex (mPFC), habenula (Hb), and ventral tegmental area (VTA) in response to Shenmen-like acupuncture. The results found that HT7 acupuncture significantly reduced ethanol consumption. Seo et al. further observed that HT7 stimulation blunted ethanol-induced increases in protein markers of microglia activity (Arginase-1, Iba-1, and Sigma-1) within the aforementioned brain regions. The authors posited that the associated changes in microglial activity in response to acupuncture may modulate neuroinflammatory processes, and thereby reduce the reinforcing effects of ethanol. The pioneering work of Seo et al. provides a promising foundation for developing and testing animals models of acupuncture in the context of AUD.
Conclusion
The integration of these four studies emphasized the potential of rodent PA and other adjunctive treatments to combat everyday barriers to health. The insights gained from these studies not only enhance our understanding of physiological and neural mechanisms in response to stress, high fat diet, and alcohol use, but provide further avenues for developing targeted, non-invasive therapies. As we continue to unravel the complexities of human disease, it remains essential to think outside of singular mechanisms and reductive, druggable targets. By leveraging advanced technologies like 3D-printing and exploring “alternative” therapies such as acupuncture, we can pave the way for more effective and personalized approaches to managing stress, substance use, and dietary challenges in our daily lives.
Statements
Author contributions
KG: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. ZU: Writing – original draft, Writing – review & editing. CP: Writing – original draft, Writing – review & editing. AO: Resources, Supervision, Writing – original draft, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
Booher W. C. Hoft N. R. Ehringer M. A. (2019). The effect of voluntary wheel running on 129/SvEvTac and C3H/Ibg alcohol consumption. Alcohol77, 91–99. 10.1016/j.alcohol.2018.10.007
2
Buhr T. J. Reed C. H. Shoeman A. Bauer E. E. Valentine R. J. Clark P. J. (2021). The influence of moderate physical activity on brain monoaminergic responses to binge-patterned alcohol ingestion in female mice. Front. Behav. Neurosci.15:12. 10.3389/fnbeh.2021.639790
3
Bullock M. L. Kiresuk T. J. Pheley A. M. Culliton P. D. Lenz S. K. (1999). Auricular acupuncture in the treatment of cocaine abuse. A study of efficacy and dosing. J. Subst. Abuse Treat.16, 31–38. 10.1016/S0740-5472(98)00002-6
4
Chang S. Kim D. H. Jang E. Y. Yoon S. S. Gwak Y. S. Yi Y. J. et al . (2019). Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus. Sci. Adv.5:eaax1342. 10.1126/sciadv.aax1342
5
Chauntry A. J. Bishop N. C. Hamer M. Paine N. J. (2022). Sedentary behaviour, physical activity and psychobiological stress reactivity: a systematic review. Biol. Psychol.172:108374. 10.1016/j.biopsycho.2022.108374
6
Crabbe J. C. Metten P. Belknap J. K. Spence S. E. Cameron A. J. Schlumbohm J. P. et al . (2014). Progress in a replicated selection for elevated blood ethanol concentrations in HDID mice. Genes Brain Behav. 13, 236–246. 10.1111/gbb.12105
7
DeVallance E. Riggs D. Jackson B. Parkulo T. Zaslau S. Chantler P. D. et al . (2017). Effect of chronic stress on running wheel activity in mice. PLoS ONE12:e0184829. 10.1371/journal.pone.0184829
8
Dishman R. K. Renner K. J. Youngstedt S. D. Reigle T. G. Bunnell B. N. Burke K. A. et al . (1997). Activity wheel running reduces escape latency and alters brain monoamine levels after footshock. Brain Res. Bull.42, 399–406. 10.1016/S0361-9230(96)00329-2
9
Ehringer M. A. Hoft N. R. Zunhammer M. (2009). Reduced alcohol consumption in mice with access to a running wheel. Alcohol43, 443–452. 10.1016/j.alcohol.2009.06.003
10
Fediuc S. Campbell J. E. Riddell M. C. (2006). Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats. J. Appl. Physiol.100, 1867–1875. 10.1152/japplphysiol.01416.2005
11
Ghosh S. Golbidi S. Werner I. Verchere B. C. Laher I. (2010). Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview. Clin. Sci.119, 57–74. 10.1042/CS20090389
12
Greenwood B. N. Fleshner M. (2011). Exercise, stress resistance, and central serotonergic systems. Exerc. Sport Sci. Rev.39, 140–149. 10.1097/JES.0b013e31821f7e45
13
Grigsby K. B. Kerr N. R. Kelty T. J. Mao X. Childs T. E. Booth F. W. (2022). Acute wheel-running increases markers of stress and aversion-related signaling in the basolateral amygdala of male rats. J. Funct. Morphol. Kinesiol.8:6. 10.3390/jfmk8010006
14
Hausmann M. F. (1932). The behavior of albino rats in choosing foods and stimulants. J. Comp. Psychol.13:279. 10.1037/h0074116
15
Jensen B. E. Townsley K. G. Grigsby K. B. Metten P. Chand M. Uzoekwe M. et al . (2021). Ethanol-related behaviors in mouse lines selectively bred for drinking to intoxication. Brain Sci.11:189. 10.3390/brainsci11020189
16
Katzmarzyk P. T. (2023). Expanding our understanding of the global impact of physical inactivity. Lancet Glob. Health11, e2–e3. 10.1016/S2214-109X(22)00482-X
17
Lightfoot J. T. Turner M. J. Daves M. Vordermark A. Kleeberger S. R. (2004). Genetic influence on daily wheel running activity level. Physiol. Genomics19, 270–276. 10.1152/physiolgenomics.00125.2004
18
Lin J.-G. Chan Y.-Y. Chen Y.-H. (2012). Acupuncture for the treatment of opiate addiction. Evid. Based Complement. Alternat. Med.2012:739045. 10.1155/2012/739045
19
McCulley W. D. Ascheid S. Crabbe J. C. Rosenwasser A. M. (2013). Selective breeding for ethanol-related traits alters circadian phenotype. Alcohol47, 187–194. 10.1016/j.alcohol.2013.01.001
20
McLellan A. T. Grossman D. S. Blaine J. D. Haverkos H. W. (1993). Acupuncture treatment for drug abuse: a technical review. J. Subst. Abuse Treat.10, 569–576. 10.1016/0740-5472(93)90061-6
21
Moraska A. Fleshner M. (2001). Voluntary physical activity prevents stress-induced behavioral depression and anti-KLH antibody suppression. Am. J. Physiol. Regul. Integr. Comp. Physiol.281, R484–R489. 10.1152/ajpregu.2001.281.2.R484
22
Mul J. D. Soto M. Cahill M. E. Ryan R. E. Takahashi H. So K. et al . (2018). Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔfosB. Neuropsychopharmacology43, 1934–1942. 10.1038/s41386-018-0103-z
23
Ozburn A. R. Harris R. A. Blednov Y. A. (2008). Wheel running, voluntary ethanol consumption, and hedonic substitution. Alcohol42, 417–424. 10.1016/j.alcohol.2008.04.006
24
Raney J. H. Testa A. Jackson D. B. Ganson K. T. Nagata J. M. (2022). Associations between adverse childhood experiences, adolescent screen time and physical activity during the COVID-19 pandemic. Acad. Pediatr.22, 1294–1299. 10.1016/j.acap.2022.07.007
25
Ruegsegger G. N. Booth F. W. (2018). Health benefits of exercise. Cold Spring Harb. Perspect. Med.8:a029694. 10.1101/cshperspect.a029694
26
Savarese A. M. Ozburn A. R. Barkley-Levenson A. M. Metten P. Crabbe J. C. (2021). The impact of drinking in the dark (DID) procedural manipulations on ethanol intake in high drinking in the dark (HDID) mice. Alcohol93, 45–56. 10.1016/j.alcohol.2021.02.001
27
Stewart C. C. (1898). Variations in daily activity produced by alcohol and by changes in barometric pressure and diet, with a description of recording methods. Am. J. Physiol.1, 40–56. 10.1152/ajplegacy.1898.1.1.40
28
Stults-Kolehmainen M. A. Sinha R. (2014). The effects of stress on physical activity and exercise. Sports Med.44, 81–12110.1007/s40279-013-0090-5
29
Tan C.-R. Qiao M. Chang J. Chen S.-M. Wang Y. (2025). Acupuncture for substance use disorders: a protocol of systematic review and meta-analysis of randomised controlled trials. BMJ Open15:e095435. 10.1136/bmjopen-2024-095435
30
Zhao Z. Kim S. C. Wu Y. Zhang J. Xu Y. Cho I. J. et al . (2014). Involvement of amygdaloid neuropeptide Y in the anxiolytic effects of acupuncture during ethanol withdrawal in rats. Neurosci. Lett.567, 19–23. 10.1016/j.neulet.2014.03.018
Summary
Keywords
adjunctive therapeutic treatment, physical activity, high fat feeding (HFF), alcohol use disorder (AUD), acupuncture
Citation
Grigsby KB, Usmani ZS, Perry CJ and Ozburn AR (2025) Editorial: The role, and underlying neural mechanisms of, physical activity in treating substance and alcohol use disorders. Front. Integr. Neurosci. 19:1589088. doi: 10.3389/fnint.2025.1589088
Received
06 March 2025
Accepted
01 May 2025
Published
30 May 2025
Volume
19 - 2025
Edited by
Elizabeth B. Torres, Rutgers, The State University of New Jersey, United States
Reviewed by
Benjamin B. Land, University of Washington, United States
Li-Lian Yuan, Des Moines University, United States
Updates
Copyright
© 2025 Grigsby, Usmani, Perry and Ozburn.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kolter B. Grigsby grigsbyk@ohsu.edu
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.