[en] Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioural markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from fully characterized. Here, 28-day-old female C57BL/6J mice were housed with (n=48) or without (n=48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a micro-PET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptors antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well-marked for long-term expression of sensitization (η²p = 0.262). Chronic administration of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η²p = 0.170) while wheel-running exercise was associated with a moderate decrease in dopamine 2/3 receptors density in striatum (η²p = 0.075), a mechanism that might contribute to protective properties of exercise against drugs of abuse vulnerability.
Research center :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Disciplines :
Neurosciences & behavior
Author, co-author :
Becker, Guillaume ; Université de Liège - ULiège > Département des sciences cliniques > Neuroimagerie des troubles de la mémoire et revalid. cogn.
De La Garza R, Yoon JH, Thompson-Lake DGY, et al. Treadmill exercise improves fitness and reduces craving and use of cocaine in individuals with concurrent cocaine and tobacco-use disorder. Psychiatry Res. 2016;245:133–140.
Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. Exercise as a novel treatment for drug addiction: A neurobiological and stage-dependent hypothesis. Neurosci Biobehav Rev. 2013;37(8): 1622–1644.
Lisha NE, Sussman S. Relationship of high school and college sports participation with alcohol, tobacco, and illicit drug use: A review. Addict Behav. 2010;35(5):399–407.
Smith MA, Schmidt KT, Iordanou JC, Mustroph ML. Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend. 2008;98(1–2):129–135.
Smith MA, Walker KL, Cole KT, Lang KC. The effects of aerobic exercise on cocaine self-administration in male and female rats. Psychopharmacology. 2011;218(2):357–369.
Smith MA, Pitts EG. Access to a running wheel inhibits the acquisition of cocaine self-administration. Pharmacol Biochem Behav. 2011;100(2):237–243.
Smith MA, Pitts EG. Wheel running decreases the positive reinforcing effects of heroin. Pharmacol Rep. 2012;64(4):960–964.
Engelmann AJ, Aparicio MB, Kim A, et al. Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase. Brain Struct Funct. 2014;219(2):657–672.
Lacy RT, Strickland JC, Brophy MK, Witte MA, Smith MA. Exercise decreases speedball self-administration. Life Sci. 2014; 114(2):86–92.
Renteria Diaz L, Siontas D, Mendoza J, Arvanitogiannis A. High levels of wheel running protect against behavioural sensitization to cocaine. Behav Brain Res. 2013;237:82–85.
Geuzaine A, Tirelli E. Wheel-running mitigates psychomotor sensitization initiation but not post-sensitization conditioned activity and conditioned place preference induced by cocaine in mice. Behav Brain Res. 2014;262:57–67.
Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev. 1993; 18(3):247–291.
Berridge KC, Robinson TE. Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol. 2016;71(8):670–679.
Schenk S, Partridge B. Sensitization and tolerance in psychostimulant self-administration. Pharmacol Biochem Behav. 1997;57(3): 543–550.
Robinson TE, Berridge KC. Addiction. Annu Rev Psychol. 2003; 54(1):25–53.
Anderson SM, Pierce RC. Cocaine-induced alterations in dopamine receptor signaling: Implications for reinforcement and reinstatement. Pharmacol Ther. 2005;106(3):389–403.
Wang GJ, Smith L, Volkow ND, et al. Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry. 2012;17(9):918–925.
Volkow ND, Fowler JS, Wolf AP, et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry. 1990;147(6):719–724.
Volkow ND. Is methylphenidate like cocaine? Arch Gen Psychiatry. 1995;52(6):456.
Kalivas PW, Duffy P, Barrow J. Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes. J Pharmacol Exp Ther. 1989;251(1):378–387.
Klitenick MA, DeWitte P, Kalivas PW. Regulation of somatodendritic dopamine release in the ventral tegmental area by opioids and GABA: an in vivo microdialysis study. J Neurosci. 1992; 12(7):2623–2632.
Lu W, Chen H, Xue C-J, Wolf ME. Repeated amphetamine administration alters the expression of mRNA for AMPA receptor subunits in rat nucleus accumbens and prefrontal cortex. Synapse. 1997; 26(3):269–280.
Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci. 1996;16(4):1550–1560.
Tanner T. GABA-induced locomotor activity in the rat, after bilateral injection into the ventral tegmental area. Neuropharmacology. 1979;18(5):441–446.
Xue C-J, Ng JP, Li Y, Wolf ME. Acute and repeated systemic amphetamine administration: effects on extracellular glutamate, aspartate, and serine levels in rat ventral tegmental area and nucleus accumbens. J Neurochem. 2002;67(1):352–363.
Will BE, Toniolo G, Brailowsky S. Unilateral infusion of GABA and saline into the nucleus basalis of rats: 1. Effects on motor function and brain morphology. Behav Brain Res. 1988;27(2):123–129.
Abel JM, Nesil T, Bakhti-Suroosh A, Grant PA, Lynch WJ. Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex. Psychopharmacology. 2019;236(7):2155–2171.
Volkow ND, Fowler JS, Wang G-J, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004;9(6):557–569.
Nader J, Claudia C, El Rawas R, et al. Loss of environmental enrichment increases vulnerability to cocaine addiction. Neuropsychopharmacology. 2012;37(7):1579–1587.
Nader MA, Czoty PW. PET imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic predisposition versus environmental modulation. Am J Psychiatry. 2005;162(8): 1473–1482.
Peris J, Boyson SJ, Cass WA, et al. Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J Pharmacol Exp Ther. 1990;253(1):38–44.
Sousa FCF, Gomes PB, Macêdo DS, Marinho MMF, Viana GSB. Early withdrawal from repeated cocaine administration upregulates muscarinic and dopaminergic D2-like receptors in rat neostriatum. Pharmacol Biochem Behav. 1999;62(1):15–20.
Maggos C. Sustained withdrawal allows normalization of in vivo [11C]N-methylspiperone dopamine D2 receptor binding after chronic binge cocaine a positron emission tomography study in rats. Neuropsychopharmacology. 1998;19(2):146–153.
Claye LH, Akunne HC, Duff Davis M, DeMattos S, Soliman KFA. Behavioral and neurochemical changes in the dopaminergic system after repeated cocaine administration. Mol Neurobiol. 1995;11(1–3):55–66.
Stanwood GD, Lucki I, McGonigle P. Differential regulation of dopamine D2 and D3 receptors by chronic drug treatments. J Pharmacol Exp Ther. 2000;295:1232–1240.
Briand LA, Flagel SB, Seeman P, Robinson TE. Cocaine self-administration produces a persistent increase in dopamine D2 High receptors. Eur Neuropsychopharmacol. 2008;18(8):551–556.
Seeman P, Ko F, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry. 2005;10(9):877–883.
Lespine L-F, Tirelli E. The protective effects of free wheel-running against cocaine psychomotor sensitization persist after exercise cessation in C57BL/6J mice. Neuroscience. 2015;310:650–664.
Lespine L-F, Tirelli E. Evidence for a long-term protection of wheel-running exercise against cocaine psychomotor sensitization in adolescent but not in adult mice. Behav Brain Res. 2018;349:63–72.
Lespine L-F, Plenevaux A, Tirelli E. Wheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring. Behav Brain Res. 2019;363: 53–60.
Lynch WJ, Robinson AM, Abel J, Smith MA. Exercise as a prevention for substance use disorder: a review of sex differences and neurobiological mechanisms. Curr Addict Reports. 2017;4:455–466.
Zhou Y, Zhao M, Zhou C, Li R. Sex differences in drug addiction and response to exercise intervention: From human to animal studies. Front Neuroendocrinol. 2016;40:24–41.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412.
Brabant C, Quertemont E, Tirelli E. Evidence that the relations between novelty-induced activity, locomotor stimulation and place preference induced by cocaine qualitatively depend upon the dose: a multiple regression analysis in inbred C57BL/6J mice. Behav Brain Res. 2005;158:201–210.
Brichard L, Ferrari V, Smith R, Aigbirhio FI. Synthesis of [18 F]-fallypride. In: Scott PJH, Hockley BG, eds. Radiochemical syntheses: radiopharmaceuticals for positron emission tomography. John Wiley & Sons, Inc., 2012:95–102.
Lemaire C, Plenevaux A, Aerts J, et al. Solid phase extraction—an alternative to the use of rotary evaporators for solvent removal in the rapid formulation of PET radiopharmaceuticals. J Label Compd Radiopharm. 1999;42(1):63–75.
Bahri MA, Plenevaux A, Warnock G, Luxen A, Seret A. NEMA NU4-2008 image quality performance report for the microPET focus 120 and for various transmission and reconstruction methods. J Nucl Med. 2009;50(10):1730–1738.
Ma Y, Hof PR, Grant SC, et al. A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy. Neuroscience. 2005;135:1203–1215.
Mirrione MM, Schiffer WK, Fowler JS, Alexoff DL, Dewey SL, Tsirka SE. A novel approach for imaging brain–behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. Neuroimage. 2007; 38:34–42.
Innis RB, Cunningham VJ, Delforge J, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–1539.
Ichise M, Liow J-S, Lu JQ, et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab. 2003;23(9):1096–1112.
Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology. 2003;28(7): 916–931.
Rosnow RL, Rosenthal R. Effect sizes. Z Psychol/J Psychol. 2009; 217(1):6–14.
Fritz CO, Morris PE, Richler JJ. Effect size estimates: current use, calculations, and interpretation. J Exp Psychol Gen. 2012;141(1): 2–18.
Franklin K, Paxinos G. The mouse brain in stereotaxic coordinates. In: The mouse brain in stereotaxic coordinates. Elsevier; 2007:xv. https://linkinghub.elsevier.com/retrieve/pii/B9780123742476500043
Smith MA, Witte MA. 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. 2012;20:437–446.
Bezard E, Dovero S, Belin D, et al. Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors. J Neurosci. 2003;23(35):10999–11007.
Solinas M, Thiriet N, El Rawas R, Lardeux V, Jaber M. Environmental enrichment during early stages of life reduces the behavioral, neurochemical, and molecular effects of cocaine. Neuropsychopharmacology. 2009;34(5):1102–1111.
Belke TW. Running and responding reinforced by the opportunity to run: effect of reinforcer duration. J Exp Anal Behav. 1997;67(3): 337–351.
Greenwood BN, Foley TE, Le TV, et al. Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway. Behav Brain Res. 2011;217(2):354–362.
Trulson ME, Ulissey MJ. Chronic cocaine administration decreases dopamine synthesis rate and increases [3H] spiroperidol binding in rat brain. Brain Res Bull. 1987;19(1):35–38.
De Vries T. Relapse to cocaine- and heroin-seeking behavior mediated by dopamine D2 receptors is time-dependent and associated with behavioral sensitization. Neuropsychopharmacology. 2002;26(1):18–26.
Seeman P, Tallerico T, Ko F, Tenn C, Kapur S. Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges. Synapse. 2002;46(4): 235–239.
Novak G, Seeman P, Le Foll B. Exposure to nicotine produces an increase in dopamine D2 High receptors: A possible mechanism for dopamine hypersensitivity. Int J Neurosci. 2010;120(11):691–697.
Liu C-L, Wang Y-K, Jin G-Z, Shi W-X, Gao M. Cocaine-induced locomotor sensitization associates with slow oscillatory firing of neurons in the ventral tegmental area. Sci Rep. 2018;8(1):1–11.
Vanderschuren LJMJ, Kalivas PW. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology. 2000;151(2-3):99–120.
Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. NeuroMolecular Med. 2008;10(2):67–80.
Kelz MB, Chen J, Carlezon WA Jr, et al. Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature. 1999;401(6750):272–276.
Pich EM, Pagliusi SR., Tessari M, Talabot-Ayer D, van Huijsduijnen RH, Chiamulera C. Common neural substrates for the addictive properties of nicotine and cocaine. Science 1997;275-(5296):83–86.
Atkins JB, Chlan-Fourney J, Nye HE, Hiroi N, Carlezon WA, Nestler EJ. Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs. Synapse. 1999;33(2):118–128.
Marques E, Vasconcelos F, Rolo MR, et al. Influence of chronic exercise on the amphetamine-induced dopamine release and neurodegeneration in the striatum of the rat. Ann N Y Acad Sci. 2008; 1139(1):222–231.
Meeusen R, Smolders I, Sarre S, et al. Endurance training effects on neurotransmitter release in rat striatum: an in vivo microdialysis study. Acta Physiol Scand. 1997;159(4):335–341.
Fisher BE, Petzinger GM, Nixon K, et al. Exercise-induced behavioral recovery and neuroplasticity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse basal ganglia. J Neurosci Res. 2004;77(3):378–390.
Mukherjee J, Constantinescu CC, Hoang AT, Jerjian T, Majji D, Pan M-L. Dopamine D3 receptor binding of 18 F-fallypride: Evaluation using in vitro and in vivo PET imaging studies. Synapse. 2015;69(12):577–591.
Volkow ND, Morales M. The brain on drugs: from reward to addiction. Cell. 2015;162(4):712–725.
Le Foll B, Diaz J, Sokoloff P. Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats. Synapse. 2003;47(3):176–183.
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76(3):470–485.
Vučcković MG, Li Q, Fisher B, et al. Exercise elevates dopamine D2 receptor in a mouse model of Parkinson’s disease: In vivo imaging with [18F]fallypride. Mov Disord. 2010;25(16):2777–2784.
Petzinger GM, Walsh JP, Akopian G, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosci. 2007;27(20):5291–5300.
Boileau I, Dagher A, Leyton M, et al. Modeling sensitization to stimulants in humans. Arch Gen Psychiatry. 2006;63(12):1386–1395.
Robertson CL, Ishibashi K, Chudzynski J, et al. Effect of exercise training on striatal dopamine D2/D3 receptors in methamphetamine users during behavioral treatment. Neuropsychopharmacology. 2016;41(61740-634X):1629–1636.
