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Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus

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Abstract

Rationale

Limited access nicotine self-administration decreases hippocampal neurogenesis, providing a mechanism for the deleterious effects of nicotine on hippocampal neuronal plasticity. However, recent studies have shown that limited access nicotine self-administration does not exhibit key features of nicotine dependence such as motivational withdrawal and increased motivation for nicotine after deprivation.

Objectives

The present study used extended access nicotine self-administration (0.03 mg/kg/infusion, 21 h/day, 4 days) with intermittent periods of deprivation (3 days) for 14 weeks, to test the hypothesis that this model enhances nicotine seeking and produces distinct responses in hippocampal neurogenesis when compared with limited access (1 h/day, 4 days) intake. Animals in the extended access group were either perfused prior to or following their final deprivation period, whereas animals in the limited access group were perfused after their last session.

Results

Limited- and extended access nicotine self-administration with periodic deprivation did not affect proliferation and differentiation of oligodendrocyte progenitors in the medial prefrontal cortex (mPFC). Conversely, extended access nicotine self-administration with periodic deprivation enhanced proliferation and differentiation of hippocampal neural progenitors. Furthermore, in the hippocampus, the number of differentiating NeuroD-labeled cells strongly and positively correlated with enhanced nicotine seeking in rats that experienced extended access nicotine self-administration.

Conclusions

These findings demonstrate that extended versus limited access to nicotine self-administration differentially affects the generation of new oligodendroglia and new neurons during adulthood. The increases in the number of differentiating cells in extended access nicotine self-administering rats may consequently contribute to aberrant hippocampal neurogenesis and may contribute to maladaptive addiction-like behaviors dependent on the hippocampus.

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References

  • Abrous DN, Adriani W, Montaron MF, Aurousseau C, Rougon G, Le Moal M, Piazza PV (2002) Nicotine self-administration impairs hippocampal plasticity. J Neurosci 22:3656–3662

    CAS  PubMed  Google Scholar 

  • Aimone JB, Wiles J, Gage FH (2009) Computational influence of adult neurogenesis on memory encoding. Neuron 61:187–202

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927

    CAS  PubMed  Google Scholar 

  • Becker S (2005) A computational principle for hippocampal learning and neurogenesis. Hippocampus 15:722–738

    Article  PubMed  Google Scholar 

  • Becker S, Macqueen G, Wojtowicz JM (2009) Computational modeling and empirical studies of hippocampal neurogenesis-dependent memory: effects of interference, stress and depression. Brain Res 1299:45–54

    Article  CAS  PubMed  Google Scholar 

  • Bora E, Yucel M, Fornito A, Pantelis C, Harrison BJ, Cocchi L, Pell G, Lubman DI (2012) White matter microstructure in opiate addiction. Addict Biol 17:141–148

    Article  CAS  PubMed  Google Scholar 

  • Borland R, Partos TR, Yong HH, Cummings KM, Hyland A (2012) How much unsuccessful quitting activity is going on among adult smokers? Data from the International Tobacco Control Four Country cohort survey. Addiction 107:673–682

    Article  PubMed Central  PubMed  Google Scholar 

  • Campbell NR, Fernandes CC, Halff AW, Berg DK (2010) Endogenous signaling through alpha7-containing nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampus. J Neurosci 30:8734–8744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cao J, Wang J, Dwyer JB, Gautier NM, Wang S, Leslie FM, Li MD (2013) Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences. Transl Psychiatry 3:e247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • CDC (2010) Center for Disease Control and Prevention. Vital signs: current cigarette smoking among adults aged ≥18 years―United States, 2009. Morb Mortal Wkly Rep 59:1135–1140

  • Cohen A, Koob GF, George O (2012) Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology 37:2153–2160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cohen A, Treweek J, Edwards S, Leao RM, Schulteis G, Koob GF, George O (2013) Extended access to nicotine leads to a CRF receptor dependent increase in anxiety-like behavior and hyperalgesia in rats. Addict Biol.

  • Cooper-Kuhn CM, Winkler J, Kuhn HG (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res 77:155–165

    Article  CAS  PubMed  Google Scholar 

  • Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited access schedule. Psychopharmacology (Berl) 99:473–478

    Article  CAS  Google Scholar 

  • Dierker L, Mermelstein R (2010) Early emerging nicotine-dependence symptoms: a signal of propensity for chronic smoking behavior in adolescents. J Pediatr 156:818–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • DiFranza JR, Savageau JA, Rigotti NA, Fletcher K, Ockene JK, McNeill AD, Coleman M, Wood C (2002) Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 11:228–235

  • Doubeni CA, Reed G, Difranza JR (2010) Early course of nicotine dependence in adolescent smokers. Pediatrics 125:1127–1133

    Article  PubMed Central  PubMed  Google Scholar 

  • Eisch AJ, Harburg GC (2006) Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology. Hippocampus 16:271–286

    Article  CAS  PubMed  Google Scholar 

  • Engelmann AJ, Aparicio MB, Kim A, Sobieraj JC, Yuan CJ, Grant Y, Mandyam CD (2013) Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase. Brain Struct Funct

  • Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317

    Article  CAS  PubMed  Google Scholar 

  • Eschenroeder AC, Vestal-Laborde AA, Sanchez ES, Robinson SE, Sato-Bigbee C (2012) Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of mu-opioid- and nociceptin/orphanin FQ receptors in cell development: implications for drug addiction treatment during pregnancy. Glia 60:125–136

    Article  PubMed Central  PubMed  Google Scholar 

  • Esposito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, Pitossi FJ, Schinder AF (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086

    Article  CAS  PubMed  Google Scholar 

  • Fields RD (2005) Myelination: an overlooked mechanism of synaptic plasticity? Neuroscientist 11:528–531

    Article  PubMed Central  PubMed  Google Scholar 

  • Fields RD (2010) Neuroscience. Change in the brain’s white matter. Science 330:768–769

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garthe A, Behr J, Kempermann G (2009) Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS ONE 4:e5464

    Article  PubMed Central  PubMed  Google Scholar 

  • Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54:559–566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O'Dell LE, Richardson HN, Koob GF (2007) CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci U S A 104:17198–17203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goldberg SR, Spealman RD, Goldberg DM (1981) Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573–575

    Article  CAS  PubMed  Google Scholar 

  • Gould E (2007) How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 8:481–488

    Article  CAS  PubMed  Google Scholar 

  • Grundey J, Thirugnanasambandam N, Kaminsky K, Drees A, Skwirba AC, Lang N, Paulus W, Nitsche MA (2012) Neuroplasticity in cigarette smokers is altered under withdrawal and partially restituted by nicotine exposition. J Neurosci 32:4156–4162

    Article  CAS  PubMed  Google Scholar 

  • Harrist A, Beech RD, King SL, Zanardi A, Cleary MA, Caldarone BJ, Eisch A, Zoli M, Picciotto MR (2004) Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor. Synapse 54:200–206

    Article  CAS  PubMed  Google Scholar 

  • Hendricks PS, Ditre JW, Drobes DJ, Brandon TH (2006) The early time course of smoking withdrawal effects. Psychopharmacology (Berl) 187:385–396

    Article  CAS  Google Scholar 

  • Hughes JR, Keenan RM, Yellin A (1989) Effect of tobacco withdrawal on sustained attention. Addict Behav 14:577–580

    Article  CAS  PubMed  Google Scholar 

  • Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW (1991) Symptoms of tobacco withdrawal. A replication and extension. Arch Gen Psychiatry 48:52–59

    Article  CAS  PubMed  Google Scholar 

  • Hughes JR, Higgins ST, Bickel WK (1994) Nicotine withdrawal versus other drug withdrawal syndromes: similarities and dissimilarities. Addiction 89:1461–1470

    Article  CAS  PubMed  Google Scholar 

  • Ide Y, Fujiyama F, Okamoto-Furuta K, Tamamaki N, Kaneko T, Hisatsune T (2008) Rapid integration of young newborn dentate gyrus granule cells in the adult hippocampal circuitry. Eur J Neurosci 28:2381–2392

    Article  PubMed  Google Scholar 

  • Jacobsen LK, Krystal JH, Mencl WE, Westerveld M, Frost SJ, Pugh KR (2005) Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers. Biol Psychiatry 57:56–66

    Article  PubMed  Google Scholar 

  • Jacobsen LK, Mencl WE, Constable RT, Westerveld M, Pugh KR (2007) Impact of smoking abstinence on working memory neurocircuitry in adolescent daily tobacco smokers. Psychopharmacology (Berl) 193:557–566

    Article  CAS  Google Scholar 

  • Jaffe JH, Kanzler M (1979) Smoking as an addictive disorder. NIDA Res Monogr 4–23

  • Kaneko N, Okano H, Sawamoto K (2006) Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb. Genes Cells 11:1145–1159

    Article  CAS  PubMed  Google Scholar 

  • Ligon KL, Kesari S, Kitada M, Sun T, Arnett HA, Alberta JA, Anderson DJ, Stiles CD, Rowitch DH (2006) Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci U S A 103:7853–7858

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lin F, Wu G, Zhu L, Lei H (2013) Heavy smokers show abnormal microstructural integrity in the anterior corpus callosum: a diffusion tensor imaging study with tract-based spatial statistics. Drug Alcohol Depend 129:82–87

    Article  CAS  PubMed  Google Scholar 

  • Mandyam CD, Koob GF (2012) The addicted brain craves new neurons: putative role for adult-born progenitors in promoting recovery. Trends Neurosci 35:250–260

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mandyam CD, Norris RD, Eisch AJ (2004) Chronic morphine induces premature mitosis of proliferating cells in the adult mouse subgranular zone. J Neurosci Res 76:783–794

    Article  CAS  PubMed  Google Scholar 

  • Mechawar N, Saghatelyan A, Grailhe R, Scoriels L, Gheusi G, Gabellec MM, Lledo PM, Changeux JP (2004) Nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb. Proc Natl Acad Sci U S A 101:9822–9826

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mendrek A, Monterosso J, Simon SL, Jarvik M, Brody A, Olmstead R, Domier CP, Cohen MS, Ernst M, London ED (2006) Working memory in cigarette smokers: comparison to non-smokers and effects of abstinence. Addict Behav 31:833–844

    Article  PubMed Central  PubMed  Google Scholar 

  • Merritt PS, Cobb AR, Moissinac L, Hirshman E (2010) Evidence that episodic memory impairment during tobacco abstinence is independent of attentional mechanisms. J Gen Psychol 137:331–342

    Article  PubMed  Google Scholar 

  • Mohapel P, Leanza G, Kokaia M, Lindvall O (2005) Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26:939–946

    Article  CAS  PubMed  Google Scholar 

  • Mudo G, Belluardo N, Mauro A, Fuxe K (2007) Acute intermittent nicotine treatment induces fibroblast growth factor-2 in the subventricular zone of the adult rat brain and enhances neuronal precursor cell proliferation. Neuroscience 145:470–483

    Article  CAS  PubMed  Google Scholar 

  • Nakauchi S, Sumikawa K (2012) Endogenously released ACh and exogenous nicotine differentially facilitate long-term potentiation induction in the hippocampal CA1 region of mice. Eur J Neurosci 35:1381–1395

    Article  PubMed  Google Scholar 

  • Nixon K (2006) Alcohol and adult neurogenesis: roles in neurodegeneration and recovery in chronic alcoholism. Hippocampus 16:287–295

    Article  CAS  PubMed  Google Scholar 

  • Nixon K, Crews FT (2004) Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. J Neurosci 24:9714–9722

    Article  CAS  PubMed  Google Scholar 

  • Noonan MA, Choi KH, Self DW, Eisch AJ (2008) Withdrawal from cocaine self-administration normalizes deficits in proliferation and enhances maturity of adult-generated hippocampal neurons. J Neurosci 28:2516–2526

    Article  CAS  PubMed  Google Scholar 

  • Noori HR, Fornal CA (2011) The appropriateness of unbiased optical fractionators to assess cell proliferation in the adult hippocampus. Front Neurosci 5:140

    Article  PubMed Central  PubMed  Google Scholar 

  • O'Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE, Markou A, Zorrilla EP, Koob GF (2007) Extended access to nicotine self-administration leads to dependence: circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320:180–193

    Article  PubMed  Google Scholar 

  • Overstreet Wadiche L, Bromberg DA, Bensen AL, Westbrook GL (2005) GABAergic signaling to newborn neurons in dentate gyrus. J Neurophysiol 94:4528–4532

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic Press, San Diego

    Google Scholar 

  • Pich EM, Pagliusi SR, Tessari M, Talabot-Ayer D, Hooft van Huijsduijnen R, Chiamulera C (1997) Common neural substrates for the addictive properties of nicotine and cocaine. Science 275:83–86

    Article  CAS  PubMed  Google Scholar 

  • Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257

    Article  CAS  PubMed  Google Scholar 

  • Recinto P, Samant AR, Chavez G, Kim A, Yuan CJ, Soleiman M, Grant Y, Edwards S, Wee S, Koob GF, George O, Mandyam CD (2012) Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration. Neuropsychopharmacology 37:1275–1287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–1401

    Article  CAS  PubMed  Google Scholar 

  • Scerri C, Stewart CA, Breen KC, Balfour DJ (2006) The effects of chronic nicotine on spatial learning and bromodeoxyuridine incorporation into the dentate gyrus of the rat. Psychopharmacology (Berl) 184:540–546

    Article  CAS  Google Scholar 

  • Seki T (2002) Hippocampal adult neurogenesis occurs in a microenvironment provided by PSA-NCAM-expressing immature neurons. J Neurosci Res 69:772–783

    Article  CAS  PubMed  Google Scholar 

  • Shingo AS, Kito S (2005) Effects of nicotine on neurogenesis and plasticity of hippocampal neurons. J Neural Transm 112:1475–1478

    Article  CAS  PubMed  Google Scholar 

  • Snyder FR, Davis FC, Henningfield JE (1989) The tobacco withdrawal syndrome: performance decrements assessed on a computerized test battery. Drug Alcohol Depend 23:259–266

    Article  CAS  PubMed  Google Scholar 

  • Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117:2–10, discussion 14-20

    Article  CAS  Google Scholar 

  • Valentine JD, Hokanson JS, Matta SG, Sharp BM (1997) Self-administration in rats allowed unlimited access to nicotine. Psychopharmacology (Berl) 133:300–304

    Article  CAS  Google Scholar 

  • Van Kampen JM, Eckman CB (2010) Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation. Neuropharmacology 58:921–929

    Article  PubMed  Google Scholar 

  • Wang LP, Kempermann G, Kettenmann H (2005) A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input. Mol Cell Neurosci 29:181–189

    Article  CAS  PubMed  Google Scholar 

  • Wei Z, Belal C, Tu W, Chigurupati S, Ameli NJ, Lu Y, Chan SL (2012) Chronic nicotine administration impairs activation of cyclic AMP-response element binding protein and survival of newborn cells in the dentate gyrus. Stem Cells Dev 21:411–422

    Article  CAS  PubMed  Google Scholar 

  • Weisz VI, Argibay PF (2009) A putative role for neurogenesis in neuro-computational terms: inferences from a hippocampal model. Cognition 112:229–240

    Article  PubMed  Google Scholar 

  • WHO (2002) World Health Organization: smoking statistics. http://www.wpro.who.int/media_centre/fact_sheets/fs_20020528.htm

  • Zhang TA, Tang J, Pidoplichko VI, Dani JA (2010) Addictive nicotine alters local circuit inhibition during the induction of in vivo hippocampal synaptic potentiation. J Neurosci 30:6443–6453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Funds from grants DA022473, AA020098, and AA06420 (CDM) and DA004398 (GFK) from the National Institute of Health and the Pearson Center for Alcoholism and Addiction Research supported the study. We acknowledge the technical assistance of Anne Phan-Huy from University of California San Diego, Jan Kirby Zabala from the Life Sciences Summer Internship Program at The Scripps Research Institute, and Ariel Feifel for assistance with processing brain tissue and immunohistochemistry. We appreciate the technical support of Elena Crawford for immunohistochemical analyses and StereoInvestigator and the editorial assistance of McKenzie Fannon. This is publication number 26032 from The Scripps Research Institute.

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Authors and Affiliations

  1. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA, 92037, USA

    Ami Cohen, Matthew T. Soleiman, Reneta Talia, George F. Koob, Olivier George & Chitra D. Mandyam

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  1. Ami Cohen
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  2. Matthew T. Soleiman
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  3. Reneta Talia
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  4. George F. Koob
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  5. Olivier George
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  6. Chitra D. Mandyam
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Corresponding author

Correspondence to Chitra D. Mandyam.

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Ami Cohen and Matthew T. Soleiman equally contributed to this article.

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Cohen, A., Soleiman, M.T., Talia, R. et al. Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus. Psychopharmacology 232, 453–463 (2015). https://doi.org/10.1007/s00213-014-3685-0

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