Abstract
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of Data and Materials
Not applicable.
References
Addy NA, Nunes EJ, Hughley SM, Small KM, Baracz SJ, Haight JL, Rajadhyaksha AM (2018) The L-type calcium channel blocker, isradipine, attenuates cueinduced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway. Neuropsychopharmacology 43:2361–2372. https://doi.org/10.1038/s41386-018-0080-2
Adell A, Artigas F (2004) The somatodendritic release of dopamine in the ventral tegmental area and its regulation by afferent transmitter systems. Neurosci Biobehav Rev 28:415–431. https://doi.org/10.1016/j.neubiorev.2004.05.001
Adinoff B (2004) Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry 12:305–320. https://doi.org/10.1080/10673220490910844
Albanese A, Minciacchi D (1983) Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. J Comp Neurol 216:406–420. https://doi.org/10.1002/cne.902160406
Antoniazzi CTD et al. (2014) Influence of neonatal tactile stimulation on amphetamine preference in young rats: parameters of addiction and oxidative stress. Pharmacol Biochem Behav 24:341–349. https://doi.org/10.1016/j.pbb.2014.07.001
Baquet ZC, Bickford PC, Jones KR (2005) Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci 25(26):6251–6259. https://doi.org/10.1523/jneurosci.4601-04.2005
Bisagno V, González B, Urbano FJ (2016) Cognitive enhancers versus addictive psychostimulants: the good and bad side of dopamine on prefrontal cortical circuits. Pharmacol Res 109:108–118. https://doi.org/10.1016/j.phrs.2016.01.013
Bourque MJ, Trudeau LE (2000) GDNF enhances the synaptic efficacy of dopaminergic neurons in culture. Eur J Neurosci 12:3172–3180. https://doi.org/10.1046/j.1460-9568.2000.00219.x
Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F, Cicchetti F (2009) Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model. Prog Neuropsychopharmacol Biol Psychiatry 33(8):1401–1408. https://doi.org/10.1016/j.pnpbp.2009.07.018
Büttner, A (2017) The neuropathology of drug abuse. Curr Opin Behav Sci 13:8–12. https://doi.org/10.1016/j.cobeha.2016.07.002
Cass WA, Walker DJ, Manning MW (1999) Augmented methamphetamine-induced overflow of striatal dopamine 1 day after GDNF administration. Brain Res 827:104–112. https://doi.org/10.1016/s0006-8993(99)01314-1
DaSilva PG, Domingues DD, de Carvalho LA, Allodi S, Correa CL (2016) Neurotrophic factors in Parkinson’s disease are regulated by exercise: evidence-based practice. J Neurol Sci 363:5–15. https://doi.org/10.1016/j.jns.2016.02.017
Di Ciano P, Robbins TW, Everitt BJ (2008) Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer. Neuropsychopharmacology 33:1413–1425. https://doi.org/10.1038/sj.npp.1301522
Dias VT, Rosa HZ, D’avila LF, Vey LT, Barcelos RCS, Burger ME (2019) Modafinil reduces amphetamine preference and prevents anxiety-like symptoms during drug withdrawal in young rats: involvement of dopaminergic targets in VTA and striatum. Prog Neuropsychopharmacol Biol Psychiatry 92:199–206. https://doi.org/10.1016/j.pnpbp.2019.01.007
Dias VT, Vey LT, Rosa HZ, D’ Avila, L.F.D., Barcelos, R.C.S., Burger, M. E., (2017) Could modafinil prevent the psychostimulant addiction? An experimental study in rats. Basic Clin Pharmacol Toxicol 121:400–408. https://doi.org/10.1111/bcpt.12821
Dinoff A, Herrmann N, Swardfager W, Lanctot KL (2017) The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: a meta-analysis. Eur J Neurosci 46:1635–1646. https://doi.org/10.1111/ejn.13603
Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489. https://doi.org/10.1038/nn1579
Galea S, Merchant RM, Lurie N (2020) The mental health consequences of COVID-19 and physical distancing: the need for prevention and early intervention. JAMA Intern Med 180(6):817–818. https://doi.org/10.1001/jamainternmed.2020.1562
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 35:157–71. https://doi.org/10.1016/2Fj.neubiorev.2009.11.009
Gomez-Pinilla F, Hillman Ch (2013) The influence of exercise on cognitive abilities. Comp Physiol 3:403–442. https://doi.org/10.1002/cphy.c110063
Graham DL, Edwards S, Bachtell RK, Dileone RJ, Rios M, Self DW (2007) Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10:1029–1037. https://doi.org/10.1038/nn1929
Harte MK, Cahir M, Reynolds GP, Gartlon JE, Jones DN (2007) Sub-chronic phencyclidine administration increases brain-derived neurotrophic factor in the RAT hippocampus. Schizophr Res 94:371–372. https://doi.org/10.1016/j.schres.2007.04.032
He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D (2005) Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption. J Neurosci 25:619–628. https://doi.org/10.1523/jneurosci.3959-04.2005
Hebert MA, Van Horne CG, Hoffer BJ, Gerhardt GA (1996) Functional effects of GDNF in normal rat striatum: presynaptic studies using in vivo electrochemistry and microdialysis. J Pharmacol Exp Ther 279:1181–1190
Heijnen S, Hommel B, Kibele A, Colzato LS (2016) Neuromodulation of aerobic exercise-a review. Front Psychol 6:1890. https://doi.org/10.3389/fpsyg.2015.01890
Intlekofer KA, Berchtold NC, Malvaez M, Carlos AJ, McQuown SC, Cunningham MJ, Wood MA, Cotman CW (2013) Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism. Neuropsychopharmacology 38(10):2027–2034. https://doi.org/10.1038/npp.2013.104
Karch SB, Drummer O (2016) Karch's Pathology of Drug Abuse, 5th ed. CRC Press, Taylor & Francis Group, Boca Raton
Kobori N, Waymire JC, Haycock JW, Clifton GL, Dash PK (2004) Enhancement of tyrosine hydroxylase phosphorylation and activity by glial cell line-derived neurotrophic factor. J Biol Chem 279:2182–2191. https://doi.org/10.1074/jbc.M310734200
Koskela M, Bäck S, Võikar V, Richie CT, Domanskyi A, Harvey BK, Airavaara M (2017) Update of neurotrophic factors in neurobiology of addiction and future directions. Neurobiol Dis 97(Pt B):189–200. https://doi.org/10.1016/j.nbd.2016.05.010
Krimer LS, Jakab RL, Goldman-Rakic PS (1997) Quantitative three-dimensional analysis of the catecholaminergic innervation of identified neurons in the macaque prefrontal córtex. J Neurosci 17:7450–7461. https://doi.org/10.1523/JNEUROSCI.17-19-07450.1997
Kuhn FT, Kr R, Antoniazzi CTD, PASE, C., Trevizol F., Barcelos, R.C.S., Dias, V.T., Roversi, K., Boufleur, N., Benvegnú D.M., Piccolo, J., Emanuelli, T., Bürger, M.E., (2013) Influence of trans fat and omega-3 on the preference of psychostimulant drugs in the first generation of young rats. Pharmacol Biochem Behav 110:58–65. https://doi.org/10.1016/j.pbb.2013.06.001
Kuhn FT, Dias VT, Kr R, Vey LT, Freitas DL, Pase CS, Roversi K, Veit JC, Emanuelli T, Burger ME (2015) Cross-generational trans fat consumption favors self-administration of amphetamine and changes molecular expressions of BDNF, DAT, and D1/D2 receptors in the cortex and hippocampus of rats. Neurotox Res 28(4):319–331. https://doi.org/10.1007/s12640-015-9549-5
Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev 71:155–234. https://doi.org/10.1152/physrev.1991.71.1.155
Lett BT, Grant VL, Koh MT, Flynn G (2002) Prior experience with wheel running produces cross-tolerance to the rewarding effect of morphine. Pharmacol Biochem Behav 72:101–105. https://doi.org/10.1016/S0091-3057(01)00722-5
Lin F, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132. https://doi.org/10.1126/science.8493557
Lu B (2003) Pro-region of neurotrophins: role in synaptic modulation. Neuron 39:735–738. https://doi.org/10.1016/s0896-6273(03)00538-5
Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y (2004) A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 24:1604–1611. https://doi.org/10.1523/jneurosci.5124-03.2004
Małczyńska P, Piotrowicz Z, Drabarek D, Langfort J, Chalimoniuk M (2019) The role of the brain-derived neurotrophic factor (BDNF) in neurodegenerative processes and in the neuroregeneration mechanisms induced by increased physical activity. Postepy Biochem 65:2–8. https://doi.org/10.18388/pb.2019_251
Mallet J, Dubertret C, Le Strat Y (2020) Addictions in the COVID-19 era: current evidence, future perspectives a comprehensive review. Progress Neuro Psychopharmacol Biol Psychiatry 110070. https://doi.org/10.1016/j.pnpbp.2020.110070
Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde Y (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11:131–133. https://doi.org/10.1038/nn2038
Maya S, Prakash T, Goli D (2018) Evaluation of neuroprotective effects of wedelolactone and gallic acid on aluminium-induced neurodegeneration: relevance to sporadic amyotrophic lateral sclerosis. Eur J Pharmacol 835:41–51. https://doi.org/10.1016/j.ejphar.2018.07.058
Meng M, Zhao X, Dang Y, Ma J, Li L, Gu S (2013) Region-specific expression of brain-derived neurotrophic factor splice variants in morphine conditioned place preference in mice. Brain Res 1519:53–62. https://doi.org/10.1016/j.brainres.2013.04.031
Messer CJ, Eisch AJ, Carlezon WA, Whisler K, Shen L, Wolf DH, Westphal H, Collins F, Russell DS, Nestler EJ (2000) Role for GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron 26:247–257. https://doi.org/10.1016/s0896-6273(00)81154-x
Mongi-Bragato B, Avalos MP, Guzmán AS, Bollati FA, Cancela LM (2018) Enkephalin as a pivotal player in neuroadaptations related to psychostimulant. Addiction Front Psychiatry 9:222. https://doi.org/10.3389/fpsyt.2018.00222
Morland C, Andersson KA, Haugen ØP, Hadzic A, Kleppa L, Gille A, Rinholm JE, Palibrk V, Diget EH, Kennedy LH, Stølen T, Hennestad E, Moldestad O, Cai Y, Puchades M, Offermanns S, Vervaeke K, Bjørås M, Wisløff U, Storm-Mathisen J, Bergersen LH (2017) Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun 23(8):15557. https://doi.org/10.1038/ncomms15557
Pascual A, Hidalgo-Figueroa M, Piruat JI, Pintado CO, Gomez-Diaz R, Lopez-Barneo J (2008) Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci 11:755–761. https://doi.org/10.1038/nn.2136
Patapoutian A, Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11:272–280. https://doi.org/10.1016/s0959-4388(00)00208-7
Paxinos G, Watson C (2007) The Rat Brain in Stereotaxic Coordinates. 6th Edition, Academic Press, San Diego
Pierce RC, Bari AA (2001) The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev Neurosci 12:95–110. https://doi.org/10.1515/revneuro.2001.12.2.95
Piotrowicz Z, Chalimoniuk M, Płoszczyca KK, Czuba M, Langfort J (2019) Acute normobaric hypoxia does not affect the simultaneous exercise induced increase in circulating BDNF and GDNF in young healthy men: a feasibility study. PLoS ONE 14(10):e0224207. https://doi.org/10.1371/journal
Rizi AA, Reisi P, Naghsh N (2016) Effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats. Adv Biomed Res 5:20. https://doi.org/10.4103/2277-9175.175906
Rosa HZ, Barcelos RCS, Segat HJ, Kr R, Dias VT, Milanesi LH, Burger ME (2020a) Physical exercise modifies behavioral and molecular parameters related to opioid addiction regardless of training time. Eur Neuropsychopharmacol 32:25–35. https://doi.org/10.1016/j.euroneuro.2019.12.111
Rosa HZ, Segat HJ, Barcelos RCS, Kr R, Rossato DR, de Brum GF, Burger ME (2020b) Involvement of the endogenous opioid system in the beneficial influence of physical exercise on amphetamine-induced addiction parameters. Pharmacol Biochem Behav 197:173000. https://doi.org/10.1016/j.pbb.2020.173000
Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233. https://doi.org/10.1016/s0301-0082(02)00016-3
Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27. https://doi.org/10.1152/jn.1998.80.1.1
Segat HJ et al. (2014) Exercise modifies amphetamine relapse: Behavioral and oxidative markers in rats. Behav Brain Res 262:94–100. https://doi.org/10.1016/j.bbr.2014.01.005
Segat HJ et al. (2016) M-Trifluoromethyl-diphenyldiselenide as a pharmacological tool to treat preference symptoms related to AMPH-induced dependence in rats. Prog Neuro-Psychoph 66:1–7. https://doi.org/10.1016/j.pnpbp.2015.11.002
Segat HJ et al. (2017) Influence of physical activity on addiction parameters of rats exposed to amphetamine which were previously supplemented with hydrogenated vegetable fat. Brain Res Bul 135:69–76. https://doi.org/10.1016/j.brainresbull.2017.09.013
Segat HJ et al. ( 2019) Substitution therapy with amphetamine-isotherapic attenuates amphetamine toxicological aspects of addiction. Neurosci Lett v. 18 690:138–144. https://doi.org/10.1016/j.neulet.2018.10.007
Sesack SR, Snyder CL, Lewis DA (1995) Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA-immunoreactive dendrites in rat and monkey córtex. J Comp Neurol 363:264–280. https://doi.org/10.1002/cne.903630208
Shen YL, Chang TY, Chang YC, Tien HH, Yang FC, Wang PY, Liao RM (2014) Elevated BDNF mRNA expression in the medial prefrontal cortex after d-amphetamine reinstated conditioned place preference in rats. Neuroscience 263:88–95. https://doi.org/10.1016/j.neuroscience.2014.01.015
Smith MA, Gergans SR, Iordanou JC, Lyle MA (2008) Chronic exercise increases sensitivity to the conditioned re- warding effects of cocaine. Pharmacol Rep 60:561–565
Spanagel R, Weiss F (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci 22:521–527. https://doi.org/10.1016/S0166-2236(99)01447-2
Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog Brain Res 128:183–191. https://doi.org/10.1016/s0079-6123(00)28016-3
Tyagi E, Zhuang Y, Agrawal R, Ying Z, Gomez-Pinilla F (2015) Interactive actions of BDNF methylation and cell metabolism for building neural resilience under the influence of diet. Neurobiol Dis 73:307–318. https://doi.org/10.1016/j.nbd.2014.09.014
Verburgh L, Ko¨nigs M., Scherder E.J., Oosterlaan J., (2014) Physical exercise and executive functions in preadolescent children, adolescents and young adults: a meta-analysis. Br J Sports Med 48:973–979. https://doi.org/10.1136/bjsports-2012-091441
Voss MV, Vivar C, Kramer AF, Van Praag H (2013) Bridging animal and human models of exercise-induced brain plasticity. Trrends Cogn Sci 17:525–544. https://doi.org/10.1016/j.tics.2013.08.001
Yang F, Feng L, Zheng F, Johnson SW, Du J, Shen L, Wu CP, Lu B (2001) GDNF acutely modulates excitability and A-type K(+) channels in midbrain dopaminergic neurons. Nat Neurosci 2001(4):1071–1078. https://doi.org/10.1038/nn734
Zoladz JA, Pilc A (2010) The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol 61:533–541
Funding
This study was financially supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES)-Finance Code 001. The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil), and Universidade Federal de Santa Maria (UFSM/PRPGP/PROAP).
Author information
Authors and Affiliations
Contributions
The authors HZR and MEB participated in carrying out and designing the study, data interpretation, and writing. The authors HZR, DRR, HJS, and KR managed the experimental procedure and molecular analysis. Authors HZR, RCSB, and MEB were responsible for the statistical analysis, data acquisition, and revision of scientific content. All authors contributed to the final approval of the version to be submitted.
Corresponding authors
Ethics declarations
Disclaimer
The funding had no further role in study design; in the collection, analysis, and data interpretation; in the report’s writing; or in the decision to submit the paper for publication.
Ethical Approval
Research involving animals—all procedures were approved by the Animal Ethics Committee of the Federal University of Santa Maria (3991221118-UFSM) and were carried out according to the Guidelines for Animal Experiments.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
H.Z., R., H.J., S., R.C.S., B. et al. Physical Exercise Promotes Beneficial Changes on Neurotrophic Factors in Mesolimbic Brain Areas After AMPH Relapse: Involvement of the Endogenous Opioid System. Neurotox Res 41, 741–751 (2023). https://doi.org/10.1007/s12640-023-00675-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-023-00675-y