Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior

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The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.

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  1. 1.

    Piazza PV, Deroche-Gamonet V. A multistep general theory of transition to addiction. Psychopharmacol (Berl). 2013;229:387–413.

  2. 2.

    Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3.

  3. 3.

    Dupret D, Revest J-M, Koehl M, Ichas F, De Giorgi F, Costet P, et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE. 2008;3:e1959.

  4. 4.

    Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cinà I, Aceti M, et al. The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol. 2008;6:e246.

  5. 5.

    Revest J-M, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza P-V, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry. 2009;14:959–67.

  6. 6.

    Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–70.

  7. 7.

    Abrous DN, Adriani W, Montaron M-F, Aurousseau C, Rougon G, Le Moal M, et al. Nicotine self-administration impairs hippocampal plasticity. J Neurosci J Soc Neurosci. 2002;22:3656–62.

  8. 8.

    Eisch AJ, Barrot M, Schad CA, Self DW, Nestler EJ. Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci USA. 2000;97:7579–84.

  9. 9.

    Andersen ML, Perry JC, Bignotto M, Perez-Mendes P, Cinini SM, Mello LEA, et al. Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1224–9.

  10. 10.

    Domínguez-Escribà L, Hernández-Rabaza V, Soriano-Navarro M, Barcia JA, Romero FJ, García-Verdugo JM, et al. Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus. Eur J Neurosci. 2006;24:586–94.

  11. 11.

    Noonan MA, Choi KH, Self DW, Eisch AJ. Withdrawal from cocaine self-administration normalizes deficits in proliferation and enhances maturity of adult-generated hippocampal neurons. J Neurosci J Soc Neurosci. 2008;28:2516–26.

  12. 12.

    Yamaguchi M, Suzuki T, Seki T, Namba T, Juan R, Arai H, et al. Repetitive cocaine administration decreases neurogenesis in adult rat hippocampus. Ann N Y Acad Sci. 2004;1025:351–62.

  13. 13.

    Mandyam CD, Wee S, Crawford EF, Eisch AJ, Richardson HN, Koob GF. Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis. Biol Psychiatry. 2008;64:958–65.

  14. 14.

    Deschaux O, Vendruscolo LF, Schlosburg JE, Diaz-Aguilar L, Yuan CJ, Sobieraj JC, et al. Hippocampal neurogenesis protects against cocaine-primed relapse. Addict Biol. 2014;19:562–74.

  15. 15.

    Lemaire V, Aurousseau C, Le Moal M, Abrous DN. Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis. Eur J Neurosci. 1999;11:4006–14.

  16. 16.

    Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA. 2000;97:11032–7.

  17. 17.

    Deminière JM, Piazza PV, Guegan G, Abrous N, Maccari S, Le Moal M, et al. Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers. Brain Res. 1992;586:135–9.

  18. 18.

    Piazza PV, Deminière JM, Le Moal M, Simon H. Factors that predict individual vulnerability to amphetamine self-administration. Science. 1989;245:1511–3.

  19. 19.

    Castilla-Ortega E, Serrano A, Blanco E, Araos P, Suárez J, Pavón FJ, et al. A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis. Neurosci Biobehav Rev. 2016;66:15–32.

  20. 20.

    Noonan MA, Bulin SE, Fuller DC, Eisch AJ. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J Neurosci J Soc Neurosci. 2010;30:304–15.

  21. 21.

    Tang FR, Loke WK, Khoo BC. Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging. Brain Dev. 2017;39:277–93.

  22. 22.

    Belka C, Budach W, Kortmann RD, Bamberg M. Radiation induced CNS toxicity--molecular and cellular mechanisms. Br J Cancer. 2001;85:1233–9.

  23. 23.

    Massa F, Koehl M, Koelh M, Wiesner T, Grosjean N, Revest J-M, et al. Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity. Proc Natl Acad Sci USA. 2011;108:6644–9.

  24. 24.

    Tronel S, Belnoue L, Grosjean N, Revest J-M, Piazza P-V, Koehl M, et al. Adult-born neurons are necessary for extended contextual discrimination. Hippocampus. 2012;22:292–8.

  25. 25.

    Martín-García E, Bourgoin L, Cathala A, Kasanetz F, Mondesir M, Gutiérrez-Rodriguez A, et al. Differential control of cocaine self-administration by GABAergic and glutamatergic CB1 cannabinoid receptors. Neuropsychopharmacology. 2016;41:2192–205.

  26. 26.

    Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162:1403–13.

  27. 27.

    Robbins TW, Ersche KD, Everitt BJ. Drug addiction and the memory systems of the brain. Ann N Y Acad Sci. 2008;1141:1–21.

  28. 28.

    Robinson TE, Flagel SB. Dissociating the predictive and incentive motivational properties of reward-related cues through the study of individual differences. Biol Psychiatry. 2009;65:869–73.

  29. 29.

    Marlatt GA. Cue exposure and relapse prevention in the treatment of addictive behaviors. Addict Behav. 1990;15:395–9.

  30. 30.

    Robinson TE, Berridge KC. Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci. 2008;363:3137–46.

  31. 31.

    Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci. 2005;8:1445–9.

  32. 32.

    Pierce RC, Kumaresan V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev. 2006;30:215–38.

  33. 33.

    Snyder JS, Kee N, Wojtowicz JM. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J Neurophysiol. 2001;85:2423–31.

  34. 34.

    Ikrar T, Guo N, He K, Besnard A, Levinson S, Hill A, et al. Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits. 2013;7:204.

  35. 35.

    Lacefield CO, Itskov V, Reardon T, Hen R, Gordon JA. Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus. 2012;22:106–16.

  36. 36.

    Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron. 2012;76:790–803.

  37. 37.

    Pascoli V, Terrier J, Espallergues J, Valjent E, O’Connor EC, Lüscher C. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature. 2014;509:459–64.

  38. 38.

    Voon V, Derbyshire K, Rück C, Irvine MA, Worbe Y, Enander J, et al. Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry. 2014;20:345–52.

  39. 39.

    Moorman DE, James MH, McGlinchey EM, Aston-Jones G. Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res. 2015;1628:130–46.

  40. 40.

    Rogers JL, See RE. Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiol Learn Mem. 2007;87:688–92.

  41. 41.

    Piazza PV, Deroche V, Rougé-Pont F, Le Moal M. Behavioral and biological factors associated with individual vulnerability to psychostimulant abuse. NIDA Res Monogr. 1998;169:105–33.

  42. 42.

    Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–61.

  43. 43.

    Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry. 2011;16:1177–88.

  44. 44.

    Anacker C, Pariante CM. Can adult neurogenesis buffer stress responses and depressive behaviour? Mol Psychiatry. 2012;17:9–10.

  45. 45.

    Opendak M, Gould E. New neurons maintain efficient stress recovery. Cell Stem Cell. 2011;9:287–8.

  46. 46.

    Lucassen PJ, Fitzsimons CP, Korosi A, Joels M, Belzung C, Abrous DN. Stressing new neurons into depression? Mol Psychiatry. 2013;18:396–7.

  47. 47.

    Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci JPN. 2004;29:185–93.

  48. 48.

    Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31:464–8.

  49. 49.

    Deroche V, Marinelli M, Le Moal M, Piazza PV. Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. J Pharmacol Exp Ther. 1997;281:1401–7.

  50. 50.

    Piazza PV, Marinelli M, Rougé-Pont F, Deroche V, Maccari S, Simon H, et al. Stress, glucocorticoids, and mesencephalic dopaminergic neurons: a pathophysiological chain determining vulnerability to psychostimulant abuse. NIDA Res Monogr. 1996;163:277–99.

  51. 51.

    Lejuez CW, Paulson A, Daughters SB, Bornovalova MA, Zvolensky MJ. The association between heroin use and anxiety sensitivity among inner-city individuals in residential drug use treatment. Behav Res Ther. 2006;44:667–77.

  52. 52.

    Belin D, Deroche-Gamonet V. Responses to novelty and vulnerability to cocaine addiction: contribution of a multi-symptomatic animal model. Cold Spring Harb Perspect Med. 2012;2:a011940.

  53. 53.

    Castilla-Ortega E, Ladrón de Guevara-Miranda D, Serrano A, Pavón FJ, Suárez J, Rodríguez de Fonseca F, et al. The impact of cocaine on adult hippocampal neurogenesis: Potential neurobiological mechanisms and contributions to maladaptive cognition in cocaine addiction disorder. Biochem Pharmacol. 2017;141:100–17.

  54. 54.

    Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang H-LL, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.

  55. 55.

    Ladrón de Guevara-Miranda D, Millón C, Rosell-Valle C, Pérez-Fernández M, Missiroli M, Serrano A, et al. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis. Dis Model Mech. 2017;10:323–36.

  56. 56.

    Chambers RA. Adult hippocampal neurogenesis in the pathogenesis of addiction and dual diagnosis disorders. Drug Alcohol Depend. 2013;130:1–12.

  57. 57.

    Taffe MA, Kotzebue RW, Crean RD, Crawford EF, Edwards S, Mandyam CD. Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates. Proc Natl Acad Sci USA. 2010;107:11104–9.

  58. 58.

    Bulin SE, Mendoza ML, Richardson DR, Song KH, Solberg TD, Yun S, et al. Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization. Addict Biol. 2017.

  59. 59.

    Chambers RA. Self DW. Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia. Neuropsychopharmacology. 2002;27:889–905.

  60. 60.

    Brady AM, McCallum SE, Glick SD, O’Donnell P. Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia. Psychopharmacology. 2008;200:205–15.

  61. 61.

    Berg SA, Czachowski CL, Chambers RA. Alcohol seeking and consumption in the NVHL neurodevelopmental rat model of schizophrenia. Behav Brain Res. 2011;218:346–9.

  62. 62.

    Recinto P, Samant ARH, Chavez G, Kim A, Yuan CJ. Soleiman M, et al. Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration. Neuropsychopharmacology. 2012;37:1275–87..

  63. 63.

    Galinato MH, Lockner JW, Fannon-Pavlich MJ, Sobieraj JC, Staples MC, Somkuwar SS, et al. A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse. Mol Psychiatry. 2017.

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This work was financially supported by INSERM, Agence Nationale pour la Recherche (to DNA: ANR n°06-NEURO-00 2-01), Aquitaine Regional Council and University of Bordeaux. This work benefited from the support of the Animal Housing and Genotyping facilities. The technical helps of Mr C Dupuy and Mrs V Roullot-Lacarrière, are gratefully acknowledged.

Author contributions:

Conception and design of experiments: PVP, DNA, VDG, JMR. Performed the experiments: JFF, EB, MK, NG, JMR. Acquisition of the data, analysis and interpretation of the data: VDG, JMR, MK, DNA, PVP. Wrote the paper: VDG, JMR, MK, DNA, PVP.


The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Author information

Author notes


    1. Neurocentre Magendie, Physiopathology of addiction and traumatic memories group, INSERM U1215, 33077, Bordeaux, France

      • Véronique Deroche-Gamonet
      • , Jean-Michel Revest
      • , Jean-François Fiancette
      • , Eric Balado
      •  & Pier-Vincenzo Piazza
    2. Université de Bordeaux, 33077, Bordeaux, France

      • Véronique Deroche-Gamonet
      • , Jean-Michel Revest
      • , Jean-François Fiancette
      • , Eric Balado
      • , Muriel Koehl
      • , Noëlle Grosjean
      • , Djoher Nora Abrous
      •  & Pier-Vincenzo Piazza
    3. Neurocentre Magendie, Neurogenesis and physiopathology group, INSERM U1215, 33077, Bordeaux, France

      • Muriel Koehl
      • , Noëlle Grosjean
      •  & Djoher Nora Abrous


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    The authors declare that they have no conflict of interest.

    Corresponding author

    Correspondence to Djoher Nora Abrous.