Abstract
Background
The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model).
Methods
Female and male rats were trained to self-administer intravenous heroin (0.015 mg/kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug- (heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking.
Results
Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions.
Conclusions
Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alizadeh M, Zahedi-Khorasani M, Miladi-Gorji H (2018) Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment. Neurosci Lett 681:73–77. https://doi.org/10.1016/j.neulet.2018.05.044
Balter RE, Dykstra LA (2012) The effect of environmental factors on morphine withdrawal in C57BL/6J mice: Running wheel access and group housing. Psychopharmacology 224:91–100. https://doi.org/10.1007/s00213-012-2826-6
Bardo MT, Compton WM (2015) Does physical activity protect against drug abuse vulnerability? Drug Alcohol Depend 153:3–13. https://doi.org/10.1016/j.drugalcdep.2015.05.037
Carroll ME, Lynch WJ (2016) How to study sex differences in addiction using animal models. Addict Biol 21:1007–1029. https://doi.org/10.1111/adb.12400
Carroll ME, Morgan AD, Lynch WJ et al (2002) Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: Phenotype and sex differences. Psychopharmacology 161:304–313. https://doi.org/10.1007/s00213-002-1030-5
Carroll ME, Smethells JR (2016) Sex differences in behavioral dyscontrol: Role in drug addiction and novel treatments. Front Psychiatry 6:1–20. https://doi.org/10.3389/fpsyt.2015.00175
Cicero TJ, Aylward SC, Meyer ER (2003) Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 74:541–549. https://doi.org/10.1016/S0091-3057(02)01039-0
Colledge F, Vogel M, Dürsteler-Macfarland K, Strom J, Schoen S, Pühse U, Gerber M (2017) A pilot randomized trial of exercise as adjunct therapy in a heroin-assisted treatment setting. J Subst Abus Treat 76:49–57. https://doi.org/10.1016/j.jsat.2017.01.012
Compton WM, Volkow ND (2006) Major increases in opioid analgesic abuse in the United States: Concerns and strategies. Drug Alcohol Depend 81:103–107. https://doi.org/10.1016/j.drugalcdep.2005.05.009
Cosgrove KP, Hunter RG, Carroll ME (2002) Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences. Pharmacol Biochem Behav 73:663–671
Cutter CJ, Schottenfeld RS, Moore BA, Ball SA, Beitel M, Savant JD, Stults-Kolehmainen MA, Doucette C, Barry DT (2014) A pilot trial of a videogame-based exercise program for methadone maintained patients. J Subst Abus Treat 47:299–305. https://doi.org/10.1016/j.jsat.2014.05.007
De Vries TJ, Binnekade R, Mulder AH, Vanderschuren LJMJ (1998) Drug induced reinstatement of heroin and cocaine seeking behaviour following long term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571. https://doi.org/10.1046/j.1460
de Wit H, Stewart J (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology 79:29–31. https://doi.org/10.1007/BF00433012
Devaud LL, Walls SA, McCulley WD, Rosenwasser AM (2012) Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats. Pharmacol Biochem Behav 103:18–25. https://doi.org/10.1016/j.pbb.2012.07.012
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278. https://doi.org/10.1073/pnas.85.14.5274
Fadaei A, Gorji HM, Hosseini SM (2015) Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats. Eur J Pharmacol 747:88–95. https://doi.org/10.1016/j.ejphar.2014.11.042
Haasova M, Warren FC, Ussher M, Janse van Rensburg K, Faulkner G, Cropley M, Byron-Daniel J, Everson-Hock ES, Oh H, Taylor AH (2013) The acute effects of physical activity on cigarette cravings: Systematic review and meta-analysis with individual participant data. Addiction 108:26–37. https://doi.org/10.1111/j.1360-0443.2012.04034.x
Lynch WJ, Abel J, Robinson AM, Smith MA (2017) Exercise as a Sex-Specific Treatment for Substance Use Disorder. Curr Addict Reports 4:467–481. https://doi.org/10.1007/s40429-017-0177-4
Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144:77–82. https://doi.org/10.1007/s002130050979
Michael J (1982) Distinguishing between discriminative and motivational functions of stimuli. J Exp Anal Behav 37:1333126. https://doi.org/10.1901/jeab.1982.37-149
Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y (2012) Anxiety profile in morphine-dependent and withdrawn rats: Effect of voluntary exercise. Physiol Behav 105:195–202. https://doi.org/10.1016/j.physbeh.2011.08.010
Mokhtari-Zaer A, Ghodrati-Jaldbakhan S, Vafaei AA, Miladi-Gorji H, Akhavan MM, Bandegi AR, Rashidy-Pour A (2014) Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats. Behav Brain Res 271:160–170. https://doi.org/10.1016/j.bbr.2014.05.061
Ogbonmwan YE, Schroeder JP, Holmes PV, Weinshenker D (2015) The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology 232:1395–1403. https://doi.org/10.1007/s00213-014-3778-9
Park Y-M, Kanaley JA, Padilla J, Zidon T, Welly RJ, Will MJ, Britton SL, Koch LG, Ruegsegger GN, Booth FW, Thyfault JP, Vieira-Potter VJ (2016) Effects of intrinsic aerobic capacity and ovariectomy on voluntary wheel running and nucleus accumbens dopamine receptor gene expression. Physiol Behav 164:383–389. https://doi.org/10.1016/j.physbeh.2016.06.006
Peterson AB, Abel JM, Lynch WJ (2014a) Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats. Psychopharmacology 231:1305–1314. https://doi.org/10.1007/s00213-013-3321-4
Peterson AB, Hivick DP, Lynch WJ (2014b) Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: Impact of sex and estrous cycle in rats. Psychopharmacology 231:2661–2670. https://doi.org/10.1007/s00213-014-3437-1
Robertson CL, Ishibashi K, Chudzynski J, Mooney LJ, Rawson RA, Dolezal BA, Cooper CB, Brown AK, Mandelkern MA, London ED (2016) Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment. Neuropsychopharmacology 41:1629–1636. https://doi.org/10.1038/npp.2015.331
Sanchez V, Lycas MD, Lynch WJ, Brunzell DH (2015) Wheel running exercise attenuates vulnerability to self-administer nicotine in rats. Drug Alcohol Depend 156:193–198. https://doi.org/10.1016/j.drugalcdep.2015.09.022
Sanchez V, Moore CF, Brunzell DH, Lynch WJ (2013) Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats. Psychopharmacology 227:403–411. https://doi.org/10.1007/s00213-012-2964-x
Sanchez V, Moore CF, Brunzell DH, Lynch WJ (2014) Sex differences in the effect of wheel running on subsequent nicotine-seeking in a rat adolescent-onset self-administration model. Psychopharmacology 231:1753–1762. https://doi.org/10.1007/s00213-013-3359-3
Schwartz RP, Jaffe JH, Highfield DA, Callaman JM, O'Grady KE (2007) A randomized controlled trial of interim methadone maintenance: 10-Month follow-up. Drug Alcohol Depend 86:30–36. https://doi.org/10.1016/j.drugalcdep.2006.04.017
Smethells JR, Swalve NL, Eberly LE, Carroll ME (2016a) Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone. Psychopharmacology 233:2999–3008. https://doi.org/10.1007/s00213-016-4345-3
Smethells JR, Zlebnik NE, Miller DK, Will MJ, Booth F, Carroll ME (2016b) Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running. Drug Alcohol Depend 167:163–168. https://doi.org/10.1016/j.drugalcdep.2016.08.020
Smith MA, Fronk GE, Abel JM, Lacy RT, Bills SE, Lynch WJ (2018) Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats. Psychopharmacology 235:1245–1255. https://doi.org/10.1007/s00213-018-4840-9
Smith MA, Lynch WJ (2012) Exercise as a potential treatment for drug abuse: Evidence from preclinical studies. Front Psychiatry 2:1–10. https://doi.org/10.3389/fpsyt.2011.00082
Smith MA, Pennock MM, Walker KL, Lang KC (2012) Access to a running wheel decreases cocaine-primed and cue-induced reinstatement in male and female rats. Drug Alcohol Depend 121:54–61. https://doi.org/10.1016/j.drugalcdep.2011.08.006
Smith MA, Pitts EG (2012) Wheel running decreases the positive reinforcing effects of heroin. Pharmacol Rep 64:960–964. https://doi.org/10.1016/j.surg.2006.10.010.Use
Stewart J, Woodside B, Shaham Y (1996) Ovarian hormones do not affect the initiation and maintenance of intravenous self-administration of heroin in the female rat. Psychobiology 24:154–159
Stoops WW, Rush CR (2014) Combination pharmacotherapies for stimulant use disorder: A review of clinical findings and recommendations for future research. Expert Rev Clin Pharmacol 7:363–374. https://doi.org/10.1586/17512433.2014.909283
Venniro M, Zhang M, Shaham Y, Caprioli D (2017) Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats. Neuropsychopharmacology 42:1126–1135. https://doi.org/10.1038/npp.2016.287
Volkow ND, Collins FS (2017) The Role of Science in Addressing the Opioid Crisis. N Engl J Med 377:391–394. https://doi.org/10.1056/NEJMsr1706626
Walker Q, Nelson CJ, Smith D, Kuhn CM (2002) Vaginal lavage attenuates cocaine-stimulated activity and establishes place preference in rats. Pharmacol Biochem Behav 73:743–752. https://doi.org/10.1016/S0091-3057(02)00883-3
Zlebnik NE, Anker JJ, Carroll ME (2012) Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats. Psychopharmacology 224:387–400. https://doi.org/10.1007/s00213-012-2760-7
Zlebnik NE, Anker JJ, Gliddon LA, Carroll ME (2010) Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats. Psychopharmacology 209:113–125. https://doi.org/10.1007/s00213-010-1776-0
Zlebnik NE, Carroll ME (2015a) Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity. Psychopharmacology 232:1049–1059. https://doi.org/10.1007/s00213-014-3744-6
Zlebnik NE, Carroll ME (2015b) Prevention of the incubation of cocaine seeking by aerobic exercise in female rats. Psychopharmacology 232:3507–3513. https://doi.org/10.1007/s00213-015-3999-6
Zlebnik NE, Hedges VL, Carroll ME, Meisel RL (2014a) Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats. Behav Brain Res 261:71–78. https://doi.org/10.1016/j.bbr.2013.12.012
Zlebnik NE, Saykao AT, Carroll ME (2014b) Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats. Psychopharmacology 231:3787–3798. https://doi.org/10.1007/s00213-014-3513-6
Zschucke E, Heinz A, Ströhle A (2012) Exercise and Physical Activity in the Therapy of Substance Use Disorders. Sci World J 2012:1–19. https://doi.org/10.1100/2012/901741
Acknowledgments
We thank Dr. Natashia Swalve for her thoughtful contributions and Jared Mitchell for his expert technical assistance conducting this research.
Funding
This study was supported by NIH/NIDA P50 DA033942 (MEC) and a NIDA training grant T32 DA007097 (JRS; PI: Dr. Thomas Molitor).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Smethells, J.R., Greer, A., Dougen, B. et al. Effects of voluntary exercise and sex on multiply-triggered heroin reinstatement in male and female rats. Psychopharmacology 237, 453–463 (2020). https://doi.org/10.1007/s00213-019-05381-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-019-05381-2