Abstract
Rationale
Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity.
Objectives
The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats.
Methods
Female rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing.
Results
Resistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose-effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core.
Conclusions
These data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguiar AF, Aguiar DH, Felisberto AD, Carani FR, Milanezi RC, Padovani CR, Dal-Pai-Silva M (2010) Effects of creatine supplementation during resistance training on myosin heavy chain (MHC) expression in rat skeletal muscle fibers. J Strength Cond Res 24(1):88–96. https://doi.org/10.1519/JSC.0b013e3181aeb103
Alderson HL, Parkinson JA, Robbins TW, Everitt BJ (2001) The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats. Psychopharmacology 153(4):455–463. https://doi.org/10.1007/s002130000634
Aparicio VA, Nebot E, Porres JM, Ortega FB, Heredia JM, López-Jurado M, Ramírez PA (2011) Effects of high-whey-protein intake and resistance training on renal, bone and metabolic parameters in rats. Br J Nutr 105(6):836–845. https://doi.org/10.1017/S0007114510004393
Aravich PF, Rieg TS, Lauterio TJ, Doerries LE (1993) Beta-endorphin and dynorphin abnormalities in rats subjected to exercise and restricted feeding: relationship to anorexia nervosa? Brain Res 622(1–2):1–8. https://doi.org/10.1016/0006-8993(93)90794-N
Art T, Franchioment P, Leukeux P (1994) Plasma beta-endorphin response of thoroughbred horses to maximal exercise. Vet Rec 135(21):499–503
Bernstein MA, Welch SP (1998) mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance. Brain Res Mol Brain Res 55(2):237–242. https://doi.org/10.1016/S0169-328X(98)00005-9
Chen JX, Zhao X, Yue GX, Wang ZF (2007) Influence of acute and chronic treadmill exercise on rat plasma lactate and brain NPY, L-ENK, DYN A1-13. Cell Mol Neurobiol 27(1):1–10. https://doi.org/10.1007/s10571-006-9110-4
Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509(7500):282–283. https://doi.org/10.1038/509282a
Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Erlbaum, Hillsdale
Collo G, Cavalleri L, Spano P (2014) Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine. Front Pharmacol 5:259. https://doi.org/10.3389/fphar.2014.00259 Review
Contet C, Kieffer BL, Befort K (2004) Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 14(3):370–378. Review. https://doi.org/10.1016/j.conb.2004.05.005
D'Cunha TM, Daoud E, Rizzo D, Bishop AB, Russo M, Mourra G, Hamel L, Sedki F, Shalev U (2016) Augmentation of heroin seeking following chronic food restriction in the rat: differential role for dopamine transmission in the nucleus accumbens shell and core. Neuropsychopharmacology 42(5):1136–1145. https://doi.org/10.1038/npp.2016.250
de Oliveira MS, da Silva Fernandes MJ, Scorza FA, Persike DS, Scorza CA, da Ponte JB et al (2010) Acute and chronic exercise modulates the expression of MOR opioid receptors in the hippocampal formation of rats. Brain Res Bull 83(5):278–283. https://doi.org/10.1016/j.brainresbull.2010.07.009
Debruille C, Luyckx M, Ballester L, Brunet C, Odou P, Dine T, Gressier B, Cazin M, Cazin JC (1999) Serum opioid activity after physical exercise in rats. Physiol Res 48(2):129–133
Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137(1–2):75–114. Review. https://doi.org/10.1016/S0166-4328(02)00286-3
Di Chiara G, Bassareo V (2007) Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol 7(1):69–76 Review. Erratum in: Current Opinion in Pharmacology 7(2): 233
Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47(Suppl 1):227–241. Review. https://doi.org/10.1016/j.neuropharm.2004.06.032
Droste SK, Schweizer MC, Ulbricht S, Reul JM (2006) Long-term voluntary exercise and the mouse hypothalamic-pituitary-adrenocortical axis: impact of concurrent treatment with the antidepressant drug tianeptine. J Neuroendocrinol 18(12):915–925. https://doi.org/10.1111/j.1365-2826.2006.01489.x
Duarte FO, Gomes-Gatto CDV, Oishi JC, Lino ADS, Stotzer US, Rodrigues MFC, Gatti da Silva GH, Selistre-de-Araújo HS (2017) Physical training improves visceral adipose tissue health by remodelling extracellular matrix in rats with estrogen absence: a gene expression analysis. Int J Exp Pathol 98(4):203–213. https://doi.org/10.1111/iep.12237
Ebal E, Cavalie H, Michaux O, Lac G (2007) Effect of a moderate exercise on the regulatory hormones of food intake in rats. Appetite 49(2):521–524. https://doi.org/10.1016/j.appet.2007.03.007
Fontana F, Bernardi P, Merlo Pich E, Boschi S, De Iasio R, Capelli M et al (1994) Endogenous opioid system and atrial natriuretic factor in normotensive offspring of hypertensive parents at rest and during exercise test. J Hypertens 12(11):1285–1290
Ghitza UE, Zhai H, Wu P, Airavaara M, Shaham Y, Lu L (2010) Role of BDNF and GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev 35(2):157–171. https://doi.org/10.1016/j.neubiorev.2009.11.009 Review
Greenwood BN, Foley TE, Le TV, Strong PV, Loughridge AB, Day HE et al (2011) Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway. Behav Brain Res 217(2):354–362. https://doi.org/10.1016/j.bbr.2010.11.005
Haraguchi FK, de Brito Magalhães CL, Neves LX, dos Santos RC, Pedrosa ML, Silva ME (2014) Whey protein modifies gene expression related to protein metabolism affecting muscle weight in resistance-exercised rats. Nutrition 30(7–8):876–881. https://doi.org/10.1016/j.nut.2013.12.007
Holroyd KB, Adrover MF, Fuino RL, Bock R, Kaplan AR, Gremel CM, Rubinstein M, Alvarez VA (2015) Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. Neuropsychopharmacology 40(6):1495–1509. https://doi.org/10.1038/npp.2014.336
Hosseini M, Alaei HA, Naderi A, Sharifi MR, Zahed R (2009) Treadmill exercise reduces self-administration of morphine in male rats. Pathophysiology 16(1):3–7. https://doi.org/10.1016/j.pathophys.2008.11.001
Houghten RA, Pratt SM, Young EA, Brown H, Spann DR (1986) Effect of chronic exercise on beta-endorphin receptor levels in rats. NIDA Res Monogr 75:505–508
Hutcheson DM, Parkinson JA, Robbins TW, Everitt BJ (2001) The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement. Psychopharmacology 153(4):464–472. https://doi.org/10.1007/s002130000635
Jacobs EH, Smit AB, de Vries TJ, Schoffelmeer AN (2005) Long-term gene expression in the nucleus accumbens following heroin administration is subregion-specific and depends on the nature of drug administration. Addict Biol 10(1):91–100. Review. https://doi.org/10.1080/13556210412331284748
Klein SL, Schiebinger L, Stefanick ML, Cahill L, Danska J, de Vries GJ, Kibbe MR, McCarthy MM, Mogil JS, Woodruff TK, Zucker I (2015) Opinion: sex inclusion in basic research drives discovery. Proc Natl Acad Sci 112(17):5257–5258. https://doi.org/10.1073/pnas.1502843112
Koo JW, Mazei-Robison MS, Chaudhury D, Juarez B, LaPlant Q, Ferguson D, Feng J, Sun H, Scobie KN, Damez-Werno D, Crumiller M, Ohnishi YN, Ohnishi YH, Mouzon E, Dietz DM, Lobo MK, Neve RL, Russo SJ, Han MH, Nestler EJ (2012) BDNF is a negative modulator of morphine action. Science 338(6103):124–128. https://doi.org/10.1126/science.1222265
Koo JW, Lobo MK, Chaudhury D, Labonté B, Friedman A, Heller E, Peña CJ, Han MH, Nestler EJ (2014) Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. Neuropsychopharmacology 39(11):2646–2653. https://doi.org/10.1038/npp.2014.118
Koo JW, Mazei-Robison MS, LaPlant Q, Egervari G, Braunscheidel KM, Adank DN, Ferguson D, Feng J, Sun H, Scobie KN, Damez-Werno DM, Ribeiro E, Peña CJ, Walker D, Bagot RC, Cahill ME, Anderson SAR, Labonté B, Hodes GE, Browne H, Chadwick B, Robison AJ, Vialou VF, Dias C, Lorsch Z, Mouzon E, Lobo MK, Dietz DM, Russo SJ, Neve RL, Hurd YL, Nestler EJ (2015) Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nat Neurosci 18(3):415–422. https://doi.org/10.1038/nn.3932
Lacy RT, Strickland JC, Brophy MK, Witte MA, Smith MA (2014) Exercise decreases speedball self-administration. Life Sci 114(2):86–92. https://doi.org/10.1016/j.lfs.2014.08.005
Lecca D, Valentini V, Cacciapaglia F, Acquas E, Di Chiara G (2007) Reciprocal effects of response contingent and noncontingent intravenous heroin on in vivo nucleus accumbens shell versus core dopamine in the rat: a repeated sampling microdialysis study. Psychopharmacology 194(1):103–116
Li X, Wolf ME (2015) Multiple faces of BDNF in cocaine addiction. Behav Brain Res 279:240–254. https://doi.org/10.1016/j.bbr.2014.11.018 Review
Li X, Rubio FJ, Zeric T, Bossert JM, Kambhampati S, Cates HM, Kennedy PJ, Liu QR, Cimbro R, Hope BT, Nestler EJ, Shaham Y (2015) Incubation of methamphetamine craving is associated with selective increases in expression of Bdnf and trkb, glutamate receptors, and epigenetic enzymes in cue-activated fos expressing dorsal striatal neurons. J Neurosci 35(21):8232–8244. https://doi.org/10.1523/JNEUROSCI.1022-15.2015
Logrip ML, Zorrilla EP, Koob GF (2012) Stress modulation of drug self-administration: implications for addiction comorbidity with post-traumatic stress disorder. Neuropharmacology 62(2):552–564. https://doi.org/10.1016/j.neuropharm.2011.07.007
Lynch WJ, Kiraly DD, Caldarone BJ, Picciotto MR, Taylor JR (2007) Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats. Psychopharmacology 191(2):263–271. https://doi.org/10.1007/s00213-006-0656-0
Lynch WJ, Piehl KB, Acosta G, Peterson AB, Hemby SE (2010) Aerobic exercise attenuates reinstatement of cocaine-seeking behavior and associated neuroadaptations in the prefrontal cortex. Biol Psychiatry 68(8):774–777. https://doi.org/10.1016/j.biopsych.2010.06.022
Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (2013) Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis. Neurosci Biobehav Rev 37(8):1622–1644. https://doi.org/10.1016/j.neubiorev.2013.06.011 Review
Mathes WF, Kanarek RB (2001) Wheel running attenuates the antinociceptive properties of morphine and its metabolite, morphine-6-glucuronide, in rats. Physiol Behav 74(1–2):245–251. https://doi.org/10.1016/S0031-9384(01)00577-7
Miller ML, Vaillancourt BD, Wright MJ Jr, Aarde SM, Vandewater SA, Creehan KM et al (2012) Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats. Drug Alcohol Depend 121(1–2):90–96. https://doi.org/10.1016/j.drugalcdep.2011.08.013
Novak CM, Burghardt PR, Levine JA (2012) The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and reward. Neurosci Biobehav Rev 36(3):1001–1014. https://doi.org/10.1016/j.neubiorev.2011.12.012
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(8):1395–1403. https://doi.org/10.1007/s00213-014-3778-9
Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinate, 7th edn. Academic Press, London
Perreault ML, Jones-Tabah J, O'Dowd BF, George SR (2013) A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signaling in rodent prefrontal cortex. Int J Neuropsychopharmacol 16(2):477–483. https://doi.org/10.1017/S1461145712000685 Epub 2012 Jul 25
Peterson AB, Abel JM, Lynch WJ (2014) Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats. Psychopharmacology 231(7):1305–1314. https://doi.org/10.1007/s00213-013-3321-4
Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19(2):67–74. https://doi.org/10.1016/S0165-6147(97)01115-2
Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci 92(26):12304–12308
Sanchez V, Moore CF, Brunzell DH, Lynch WJ (2013) Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats. Psychopharmacology 227(3):403–411. https://doi.org/10.1007/s00213-012-2964-x
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
Schmidt HD, Sangrey GR, Darnell SB, Schassburger RL, Cha JH, Pierce RC et al (2012) Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters. J Neurochem 120(2):202–209. https://doi.org/10.1111/j.1471-4159.2011.07571.x
Self DW (2004) Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47(Suppl 1):242–255. Review. https://doi.org/10.1016/j.neuropharm.2004.07.005
Self DW (2010) Dopamine receptor subtypes in reward and relapse. In: Neve KA (ed) The dopamine receptors, 2nd edn. Humana Press, New York, pp 479–524. https://doi.org/10.1007/978-1-60327-333-6_17
Shippenberg TS, LeFevour A, Chefer VI (2008) Targeting endogenous mu- and delta-opioid receptor systems for the treatment of drug addiction. CNS Neurol Disord Drug Targets 7(5):442–453. Review. https://doi.org/10.2174/187152708786927813
Smith MA, Lyle MA (2006) Chronic exercise decreases sensitivity to mu opioids in female rats: correlation with exercise output. Pharmacol Biochem Behav 85(1):12–22. https://doi.org/10.1016/j.pbb.2006.06.020
Smith MA, Lynch WJ (2012) Exercise as a potential treatment for drug abuse: evidence from preclinical studies. Front Psychiatry 2:82. https://doi.org/10.3389/fpsyt.2011.00082
Smith MA, Pitts EG (2012) Wheel running decreases the positive reinforcing effects of heroin. Pharmacol Rep 64(4):960–964. https://doi.org/10.1016/S1734-1140(12)70891-5
Smith MA, Witte MA (2012) The effects of exercise on cocaine self-administration, food-maintained responding, and locomotor activity in female rats: importance of the temporal relationship between physical activity and initial drug exposure. Exp Clin Psychopharmacol 20(6):437–446. https://doi.org/10.1037/a0029724
Smith MA, Schmidt KT, Iordanou JC, Mustroph ML (2008) Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend 98(1–2):129–135. https://doi.org/10.1016/j.drugalcdep.2008.05.006
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(1–2):54–61. https://doi.org/10.1016/j.drugalcdep.2011.08.006
Sobieraj JC, Kim A, Fannon MJ, Mandyam CD (2016) Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221(1):261–276. https://doi.org/10.1007/s00429-014-0905-7
Strickland JC, Smith MA (2016) Animal models of resistance exercise and their application to neuroscience research. J Neurosci Methods 273:191–200. https://doi.org/10.1016/j.jneumeth.2016.08.003
Strickland JC, Abel JM, Lacy RT, Beckmann JS, Witte MA, Lynch WJ, Smith MA (2016) The effects of resistance exercise on cocaine self-administration, muscle hypertrophy, and BDNF expression in the nucleus accumbens. Drug Alcohol Depend 163:186–194. https://doi.org/10.1016/j.drugalcdep.2016.04.019
Tao PL, Han KF, Wang SD, Lue WM, Elde R, Law PY (1998) Immunohistochemical evidence of down-regulation of mu-opioid receptor after chronic PL-017 in rats. Eur J Pharmacol 344(2–3):137–142. https://doi.org/10.1016/S0014-2999(97)01596-3
Terwilliger RZ, Beitner-Johnson D, Sevarino KA, Crain SM, Nestler EJ (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 548(1–2):100–110. https://doi.org/10.1016/0006-8993(91)91111-D
Walder RY, Wattiez AS, White SR, Marquez de Prado B, Hamity MV, Hammond DL (2014) Validation of four reference genes for quantitative mRNA expression studies in a rat model of inflammatory injury. Mol Pain 10:55. https://doi.org/10.1186/1744-8069-10-55
Wilson W, Marsden C (1995) Extracellular dopamine in the nucleus accumbens of the rat during treadmill running. Acta Physiol Scand 155(4):465–466. https://doi.org/10.1111/j.1748-1716.1995.tb09997.x
Wingo T, Nesil T, Chang SL, Li MD (2016) Interactive effects of ethanol and HIV-1 proteins on novelty seeking behaviors and addiction-related gene expression. Alcohol Clin Exp Res 40(10):2102–2113. https://doi.org/10.1111/acer.13206
Wise RA, Leone P, Rivest R, Leeb K (1995) Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration. Synapse 21(2):140–148. https://doi.org/10.1002/syn.890210207
Zahm DS (1999) Functional-anatomical implications of the nucleus accumbens core and shell subterritories. Ann N Y Acad Sci 877(1 ADVANCING FRO):113–128. Review. https://doi.org/10.1111/j.1749-6632.1999.tb09264.x
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(1):113–125. https://doi.org/10.1007/s00213-010-1776-0
Acknowledgements
The authors thank the National Institute on Drug Abuse for supplying the study drug.
Funding
This study was funded by NIH Grants DA027485 (MAS), DA031725 (MAS), and DA039093 (WJL). The NIH had no role in the design of the study; in the collection, analysis, and interpretation of the data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Contributions
M.A. Smith developed the model and conceived the project. G.E. Fronk, S.E. Bills, and R.T. Lacy collected the behavioral data and assisted in data analysis and interpretation. J.M. Abel and W.J. Lynch collected the molecular data and assisted in data analysis and interpretation. M.A. Smith, G.E. Fronk, and W.J. Lynch drafted the manuscript. All authors approved the manuscript for submission.
Corresponding author
Ethics declarations
All rats were maintained in accordance with the guidelines of the Animal Care and Use Committee of Davidson College.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Smith, M.A., Fronk, G.E., Abel, J.M. et al. Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats. Psychopharmacology 235, 1245–1255 (2018). https://doi.org/10.1007/s00213-018-4840-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-018-4840-9