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The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats

Abstract

Rationale

Voluntary aerobic exercise has shown promise as a treatment for substance abuse, reducing relapse in cocaine-dependent people. Wheel running also attenuates drug-primed and cue-induced reinstatement of cocaine seeking in rats, an animal model of relapse. However, in most of these studies, wheel access was provided throughout cocaine self-administration and/or extinction and had effects on several parameters of drug seeking. Moreover, the effects of exercise on footshock stress-induced reinstatement have not been investigated.

Objectives

The purposes of this study were to isolate and specifically examine the protective effect of exercise on relapse-like behavior elicited by a drug prime or stress.

Methods

Rats were trained to self-administer cocaine at a stable level, followed by extinction training. Once extinction criteria were met, rats were split into exercise (24 h, continuous access to running wheel) and sedentary groups for 3 weeks, after which, drug-seeking behavior was assessed following a cocaine prime or footshock. We also measured galanin messenger RNA (mRNA) in the locus coeruleus and A2 noradrenergic nucleus.

Results

Exercising rats ran ∼4–6 km/day, comparable to levels previously reported for rats without a history of cocaine self-administration. Post-extinction exercise significantly attenuated cocaine-primed, but not footshock stress-induced, reinstatement of cocaine seeking, and increased galanin mRNA expression in the LC but not A2.

Conclusion

These results indicate that chronic wheel running can attenuate some forms of reinstatement, even when initiated after the cessation of cocaine self-administration, supporting the idea that voluntary exercise programs may help maintain abstinence in clinical populations.

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References

  • Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Smith PJ, Hoffman BM, O’Hayer CV, Mabe S, Johnson J, Doraiswamy PM, Jiang W, Schocken DD, Hinderliter AL (2012) Exercise and pharmacological treatment of depressive symptoms in patients with coronary heart disease: results from the UPBEAT (Understanding the Prognostic Benefits of Exercise and Antidepressant Therapy) study. J Am Coll Cardiol 60:1053–1063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brown ZJ, Tribe E, D’Souza NA, Erb S (2009) Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 203:121–130

    Article  CAS  Google Scholar 

  • Brown RA, Abrantes AM, Read JP, Marcus BH, Jakicic J, Strong DR, Oakley JR, Ramsey SE, Kahler CW, Stuart GG, Dubreuil ME, Gordon AA (2010) A pilot study of aerobic exercise as an adjunctive treatment for drug dependence. Mental Health Phys Act 3:27–34

    Article  Google Scholar 

  • Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013) Exercise for depression. Cochrane Data Syst Rev 9:CD004366

  • Epps SA, Kahn AB, Holmes PV, Boss-Williams KA, Weiss JM, Weinshenker D (2013) Antidepressant and anticonvulsant effects of exercise in a rat model of epilepsy and depression comorbidity. Epilepsy Behav 29:47–52

    Article  PubMed Central  PubMed  Google Scholar 

  • Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J (2000) Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology 23:138–150

    Article  CAS  PubMed  Google Scholar 

  • Gaval-Cruz M, Weinshenker D (2009) mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 9:175–187

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hawes JJ, Brunzell DH, Narasimhaiah R, Langel U, Wynick D, Picciotto MR (2008) Galanin protects against behavioral and neurochemical correlates of opiate reward. Neuropsychopharmacology 33:1864–1873

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Holmes A, Picciotto MR (2006) Galanin: a novel therapeutic target for depression, anxiety disorders and drug addiction? CNS Neurol Disord Drug Targets 5:225–232

    Article  CAS  PubMed  Google Scholar 

  • Holmes PV, Yoo HS, Dishman RK (2006) Voluntary exercise and clomipramine treatment elevate prepro-galanin mRNA levels in the locus coeruleus in rats. Neurosci Lett 408:1–4

    Article  CAS  PubMed  Google Scholar 

  • Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 127:25–53

    CAS  PubMed  Google Scholar 

  • Kupferschmidt DA, Brown ZJ, Erb S (2011) A procedure for studying the footshock-induced reinstatement of cocaine seeking in laboratory rats. J Visual Exp. doi:10.3791/2265

  • Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718

    CAS  PubMed  Google Scholar 

  • 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 68:774–777

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 37:1622–1644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mejias-Aponte CA, Drouin C, Aston-Jones G (2009) Adrenergic and noradrenergic innervation of the midbrain ventral tegmental area and retrorubral field: prominent inputs from medullary homeostatic centers. J Neurosci 29:3613–3626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mitrano DA, Schroeder JP, Smith Y, Cortright JJ, Bubula N, Vezina P, Weinshenker D (2012) Alpha-1 Adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission. Neuropsychopharmacology 37:2161–2172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murray PS, Groves JL, Pettett BJ, Britton SL, Koch LG, Dishman RK, Holmes PV (2010) Locus coeruleus galanin expression is enhanced after exercise in rats selectively bred for high capacity for aerobic activity. Peptides 31:2264–2268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Narasimhaiah R, Kamens HM, Picciotto MR (2009) Effects of galanin on cocaine-mediated conditioned place preference and ERK signaling in mice. Psychopharmacology (Berl) 204:95–102

    Article  CAS  Google Scholar 

  • Ogbonmwan YE, Sciolino NR, Groves-Chapman JL, Freeman KG, Schroeder JP, Edwards GL, Holmes PV, Weinshenker D (2014) The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex. Addict Biol. doi:10.1111/adb.12166

  • O’Neal HA, Van Hoomissen JD, Holmes PV, Dishman RK (2001) Prepro-galanin messenger RNA levels are increased in rat locus coeruleus after treadmill exercise training. Neurosci Lett 299:69–72

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press Limited, London

    Google Scholar 

  • 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 (Berl) 231:1305–1314

    Article  CAS  Google Scholar 

  • Picciotto MR (2008) Galanin and addiction. Cell Mol Life Sci 65:1872–1879

    Article  CAS  PubMed  Google Scholar 

  • Reiss JI, Dishman RK, Boyd HE, Robinson JK, Holmes PV (2009) Chronic activity wheel running reduces the severity of kainic acid-induced seizures in the rat: possible role of galanin. Brain Res 1266:54–63

    Article  CAS  PubMed  Google Scholar 

  • Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine beta-hydroxylase. Neuropsychopharmacology 35:2440–2449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schroeder JP, Epps SA, Grice TW, Weinshenker D (2013) The selective dopamine beta-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior. Neuropsychopharmacology 38:1032–1038

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sciolino NR, Holmes PV (2012) Exercise offers anxiolytic potential: a role for stress and brain noradrenergic-galaninergic mechanisms. Neurosci Biobehav Rev 36:1965–1984

    Article  CAS  PubMed  Google Scholar 

  • Sciolino NR, Dishman RK, Holmes PV (2012) Voluntary exercise offers anxiolytic potential and amplifies galanin gene expression in the locus coeruleus of the rat. Behav Brain Res 233:191–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sciolino NR, Smith JM, Stranahan AM, Freeman KG, Edwards GL, Weinshenker D, Holmes PV (2014) Galanin mediates features of neural and behavioral stress resilience afforded by exercise. Neuropharmacology. doi: 10.1016/j.neuropharm.2014.09.029

  • Shaham Y, Highfield D, Delfs J, Leung S, Stewart J (2000) Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons. Eur J Neurosci 12:292–302

    Article  CAS  PubMed  Google Scholar 

  • Simon H, Le Moal M, Stinus L, Calas A (1979) Anatomical relationships between the ventral mesencephalic tegmentum—a 10 region and the locus coeruleus as demonstrated by anterograde and retrograde tracing techniques. J Neural Transm 44:77–86

    Article  CAS  PubMed  Google Scholar 

  • Sinyor D, Brown T, Rostant L, Seraganian P (1982) The role of a physical fitness program in the treatment of alcoholism. J Stud Alcohol 43:380–386

    Article  CAS  PubMed  Google Scholar 

  • Smith RJ, Aston-Jones G (2011) Alpha(2) adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. Biol Psychiatry 70:712–719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith MA, Pitts EG (2011) Access to a running wheel inhibits the acquisition of cocaine self-administration. Pharmacol Biochem Behav 100:237–243

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith MA, Schmidt KT, Iordanou JC, Mustroph ML (2008) Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend 98:129–135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith MA, Walker KL, Cole KT, Lang KC (2011) The effects of aerobic exercise on cocaine self-administration in male and female rats. Psychopharmacology (Berl) 218:357–369

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Van Hoomissen JD, Holmes PV, Zellner AS, Poudevigne A, Dishman RK (2004) Effects of beta-adrenoreceptor blockade during chronic exercise on contextual fear conditioning and mRNA for galanin and brain-derived neurotrophic factor. Behav Neurosci 118:1378–1390

    Article  PubMed  Google Scholar 

  • Veale D, Le Fevre K, Pantelis C, de Souza V, Mann A, Sargeant A (1992) Aerobic exercise in the adjunctive treatment of depression: a randomized controlled trial. J R Soc Med 85:541–544

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ventura R, Morrone C, Puglisi-Allegra S (2007) Prefrontal/accumbal catecholamine system determines motivational salience attribution to both reward- and aversion-related stimuli. Proc Natl Acad Sci U S A 104:5181–5186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vila-Porcile E, Xu ZQ, Mailly P, Nagy F, Calas A, Hokfelt T, Landry M (2009) Dendritic synthesis and release of the neuropeptide galanin: morphological evidence from studies on rat locus coeruleus neurons. J Comp Neurol 516:199–212

    Article  CAS  PubMed  Google Scholar 

  • Weinshenker D, Schroeder JP (2007) There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32:1433–1451

    Article  CAS  PubMed  Google Scholar 

  • Weinstock J, Barry D, Petry NM (2008) Exercise-related activities are associated with positive outcome in contingency management treatment for substance use disorders. Addict Behav 33:1072–1075

    Article  PubMed Central  PubMed  Google Scholar 

  • Weiss JM, Boss-Williams KA, Moore JP, Demetrikopoulos MK, Ritchie JC, West CH (2005) Testing the hypothesis that locus coeruleus hyperactivity produces depression-related changes via galanin. Neuropeptides 39:281–287

    Article  CAS  PubMed  Google Scholar 

  • Xu ZQ, Zheng K, Hokfelt T (2005) Electrophysiological studies on galanin effects in brain—progress during the last six years. Neuropeptides 39:269–275

    Article  CAS  PubMed  Google Scholar 

  • Zachariou V, Brunzell DH, Hawes J, Stedman DR, Bartfai T, Steiner RA, Wynick D, Langel U, Picciotto MR (2003) The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal. Proc Natl Acad Sci U S A 100:9028–9033

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang XY, Kosten TA (2005) Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking. Biol Psychiatry 57:1202–1204

    Article  CAS  PubMed  Google Scholar 

  • Zlebnik NE, Anker JJ, Gliddon LA, Carroll ME (2010) Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats. Psychopharmacology (Berl) 209:113–125

    Article  CAS  Google Scholar 

  • Zlebnik NE, Anker JJ, Carroll ME (2012) Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats. Psychopharmacology (Berl) 224:387–400

    Article  CAS  Google Scholar 

  • Zlebnik NE, Hedges VL, Carroll ME, Meisel RL (2014) Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats. Behav Brain Res 261:71–78

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Cheryl Strauss for the helpful editing of the manuscript. This work was supported by the National Institute of Drug Abuse (DA027535 to DW and PVH, DA033091 and DA015040 to YEO).

Conflict of interest

DW is co-inventor on a patent concerning the use of selective dopamine β-hydroxylase inhibitors for the treatment of cocaine dependence (US-2010-0105748-A1; “Methods and Compositions for Treatment of Drug Addiction”). The other authors declare no conflicts of interest.

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Correspondence to David Weinshenker.

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Ogbonmwan, Y.E., Schroeder, J.P., Holmes, P.V. et al. The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology 232, 1395–1403 (2015). https://doi.org/10.1007/s00213-014-3778-9

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  • DOI: https://doi.org/10.1007/s00213-014-3778-9

Keywords

  • Cocaine
  • Rat
  • Reinstatement
  • Exercise
  • Stress
  • Locus coeruleus