Skip to main content

Impact of short access nicotine self-administration on expression of α4β2* nicotinic acetylcholine receptors in non-human primates

Abstract

Rationale

Although nicotine exposure upregulates the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs), the upregulation of nAChRs in non-human primates voluntarily self-administering nicotine has never been demonstrated.

Objectives

The objective of the study is to determine if short access to nicotine in a non-human primate model of nicotine self-administration is sufficient to induce nAChRs upregulation.

Methods

We combined a nicotine self-administration paradigm with in vivo measure of α4β2* nAChRs using 2-[18F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in six squirrel monkeys. PET measurement was performed before and after intravenous nicotine self-administration (unit dose 10 μg/kg per injection). Monkeys were trained to self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Intermittent access (1 h daily per weekday) to nicotine was allowed for 4 weeks and levels of α4β2* nAChRs were measured 4 days later.

Results

This intermittent access was sufficient to induce upregulation of α4β2* receptors in the whole brain (31 % upregulation) and in specific brain areas (+36 % in amygdala and +62 % in putamen).

Conclusions

These results indicate that intermittent nicotine exposure is sufficient to produce change in nAChRs expression.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  • Benwell ME, Balfour DJ, Anderson JM (1988) Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247

    CAS  Article  PubMed  Google Scholar 

  • Besson M, Granon S, Mameli-Engvall M, Cloez-Tayarani I, Maubourguet N, Cormier A, Cazala P, David V, Changeux JP, Faure P (2007) Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci U S A 104:8155–8160

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282:7–13

    CAS  PubMed  Google Scholar 

  • Brody AL, Mukhin AG, La Charite J, Ta K, Farahi J, Sugar CA, Mamoun MS, Vellios E, Archie M, Kozman M, Phuong J, Arlorio F, Mandelkern MA (2013) Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. Int J Neuropsychopharmacol 16:957–966

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Brody AL, Mukhin AG, Mamoun MS, Luu T, Neary M, Liang L, Shieh J, Sugar CA, Rose JE, Mandelkern MA (2014) Brain nicotinic acetylcholine receptor availability and response to smoking cessation treatment: a randomized trial. JAMA Psychiatry 71:797–805

    Article  PubMed  PubMed Central  Google Scholar 

  • Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS, Horti AG, Mukhin AG (2003) Graphical analysis of 2-[18F]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain. Synapse 48:25–34

    CAS  Article  PubMed  Google Scholar 

  • Department of Health and Human Services (1988) The Health Consequences of Smoking. Nicotine Addiction. Department of Health and Human Services (DHHS) Publication No. (CDC) 88–8406, Washington DC

  • Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41:31–37

    CAS  PubMed  Google Scholar 

  • Flores CM, Davila-Garcia MI, Ulrich YM, Kellar KJ (1997) Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochem 69:2216–2219

    CAS  Article  PubMed  Google Scholar 

  • Gergen GA, MacLean PD (1962) A Stereotaxic atlas of the Brain of the squirrel monkey (Saimiri Sciureus), U.S. Department of Health, Education, and Welfare. Public Health Service. National Institutes of Health. Bethesda, Maryland. U.S. Government Printing Office. Washington, D.C.

  • Goodwin AK, Hiranita T, Paule MG (2015) The reinforcing effects of nicotine in humans and nonhuman primates: a review of intravenous self-administration evidence and future directions for research. Nicotine Tob Res 17(11):1297–310

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

    CAS  Article  PubMed  Google Scholar 

  • Gould RW, Duke AN, Nader MA (2014) PET studies in nonhuman primate models of cocaine abuse: translational research related to vulnerability and neuroadaptations. Neuropharmacology 84:138–151

    CAS  Article  PubMed  Google Scholar 

  • Govind AP, Vezina P, Green WN (2009) Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 78:756–765

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Horti AG, Scheffel U, Koren AO, Ravert HT, Mathews WB, Musachio JL, Finley PA, London ED, Dannals RF (1998) 2-[18F]Fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors. Nucl Med Biol 25:599–603

    CAS  Article  PubMed  Google Scholar 

  • Horti AG, Kuwabara H, Holt DP, Dannals RF, Wong DF (2013) Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors. J Label Compd Radiopharm 56:159–166

    CAS  Article  Google Scholar 

  • Howell LL, Wilcox KM (2002) Functional imaging and neurochemical correlates of stimulant self-administration in primates. Psychopharmacology (Berlin) 163:352–361

    CAS  Article  Google Scholar 

  • Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539

    CAS  Article  PubMed  Google Scholar 

  • Jacobs EH, Smit AB, de Vries TJ, Schoffelmeer AN (2003) Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol Sci 24:566–573

    CAS  Article  PubMed  Google Scholar 

  • Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME, Mascia P, Bandiera T, Armirotti A, Bertorelli R, Chefer SI, Barnes C, Yasar S, Piomelli D, Goldberg SR (2015a) Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40:2185–2197

    CAS  Article  PubMed  Google Scholar 

  • Justinova Z, Le Foll B, Redhi GH, Markou A, Goldberg SR (2015a) Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology (Berlin)

  • Kimes AS, Horti AG, London ED, Chefer SI, Contoreggi C, Ernst M, Friello P, Koren AO, Kurian V, Matochik JA, Pavlova O, Vaupel DB, Mukhin AG (2003) 2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans. FASEB J Off Publ Fed Am Soc Exp Biol 17:1331–1333

    CAS  Google Scholar 

  • Kuryatov A, Luo J, Cooper J, Lindstrom J (2005) Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol 68:1839–1851

    CAS  PubMed  Google Scholar 

  • Le Foll B, Chefer SI, Kimes AS, Shumway D, Goldberg SR, Stein EA, Mukhin AG (2007a) Validation of an extracerebral reference region approach for the quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-18F-fluoro-A-85380. J Nucl Med 48:1492–1500

    Article  PubMed  Google Scholar 

  • Le Foll B, Wertheim C, Goldberg SR (2007b) High reinforcing efficacy of nicotine in non-human primates. PLoS ONE 2:e230

    Article  PubMed  PubMed Central  Google Scholar 

  • Le Foll B, Chefer SI, Kimes AS, Shumway D, Stein EA, Mukhin AG, Goldberg SR (2009) Baseline expression of alpha4beta2* nicotinic acetylcholine receptors predicts motivation to self-administer nicotine. Biol Psychiatry 65:714–716

    Article  PubMed  PubMed Central  Google Scholar 

  • Lester HA, Xiao C, Srinivasan R, Son CD, Miwa J, Pantoja R, Banghart MR, Dougherty DA, Goate AM, Wang JC (2009) Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS J 11:167–177

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lomazzo E, Hussmann GP, Wolfe BB, Yasuda RP, Perry DC, Kellar KJ (2011) Effects of chronic nicotine on heteromeric neuronal nicotinic receptors in rat primary cultured neurons. J Neurochem 119:153–164

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Marks MJ, Burch JB, Collins AC (1983) Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther 226:817–825

    CAS  PubMed  Google Scholar 

  • Mascia P, Pistis M, Justinova Z, Panlilio LV, Luchicchi A, Lecca S, Scherma M, Fratta W, Fadda P, Barnes C, Redhi GH, Yasar S, Le Foll B, Tanda G, Piomelli D, Goldberg SR (2011) Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry 69:633–641

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloez-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Faure P, Granon S, Changeux JP (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436:103–107

    CAS  Article  PubMed  Google Scholar 

  • Mukhin AG, Kimes AS, Chefer SI, Matochik JA, Contoreggi CS, Horti AG, Vaupel DB, Pavlova O, Stein EA (2008) Greater nicotinic acetylcholine receptor density in smokers than in nonsmokers: a PET study with 2-18F-FA-85380. J Nucl Med 49:1628–1635

    Article  PubMed  PubMed Central  Google Scholar 

  • Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552

    CAS  PubMed  Google Scholar 

  • Picciotto MR, Mineur YS (2014) Molecules and circuits involved in nicotine addiction: The many faces of smoking. Neuropharmacology 76(Pt B):545–553

    CAS  Article  PubMed  Google Scholar 

  • Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177

    CAS  Article  PubMed  Google Scholar 

  • Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84:329–342

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Schwartz RD, Kellar KJ (1983) Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science 220:214–216

    CAS  Article  PubMed  Google Scholar 

  • Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, Perry E, Dubin JA, Estok K, Brenner E, Baldwin RM, Tamagnan GD, Seibyl JP, Jatlow P, Picciotto MR, London ED, O’Malley S, van Dyck CH (2006) Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci 26:8707–8714

    CAS  Article  PubMed  Google Scholar 

  • Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C, Whiteaker P, Marks MJ, Collins AC, Lester HA (2004) Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 306:1029–1032

    CAS  Article  PubMed  Google Scholar 

  • Valette H, Bottlaender M, Dolle F, Coulon C, Ottaviani M, Syrota A (2003) Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys. J Neurochem 84:105–111

    CAS  Article  PubMed  Google Scholar 

  • Valette H, Bottlaender M, Dolle F, Coulon C, Ottaviani M, Syrota A (2005) Acute effects of physostigmine and galantamine on the binding of [18F]fluoro-A-85380: a PET study in monkeys. Synapse 56:217–221

    CAS  Article  PubMed  Google Scholar 

  • Vaupel DB, Stein EA, Mukhin AG (2007) Quantification of alpha4beta2* nicotinic receptors in the rat brain with microPET and 2-[18F]F-A-85380. Neuroimage 34:1352–1362

    Article  PubMed  PubMed Central  Google Scholar 

  • Wonnacott S (1990) The paradox of nicotinic acetylcholine receptor upregulation by nicotine. Trends Pharmacol Sci 11:216–219

    CAS  Article  PubMed  Google Scholar 

  • Wullner U, Gundisch D, Herzog H, Minnerop M, Joe A, Warnecke M, Jessen F, Schutz C, Reinhardt M, Eschner W, Klockgether T, Schmaljohann J (2008) Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain. Neurosci Lett 430:34–37

    Article  PubMed  Google Scholar 

  • Zambrano CA, Salamander RM, Collins AC, Grady SR, Marks MJ (2012) Regulation of the distribution and function of [(125)I]epibatidine binding sites by chronic nicotine in mouse embryonic neuronal cultures. J Pharmacol Exp Ther 342:245–254

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Zambrano CA, Short CA, Salamander RM, Grady SR, Marks MJ (2015) Density of alpha4beta2* nAChR on the surface of neurons is modulated by chronic antagonist exposure. Pharmacol Res Perspect 3:e00111

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernard Le Foll.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Financial support

This study was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS.

Additional information

Steven R. Goldberg In memoriam

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Le Foll, B., Chefer, S.I., Kimes, A.S. et al. Impact of short access nicotine self-administration on expression of α4β2* nicotinic acetylcholine receptors in non-human primates. Psychopharmacology 233, 1829–1835 (2016). https://doi.org/10.1007/s00213-016-4250-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4250-9

Keywords

  • Positron emission tomography
  • Nicotine self-administration
  • In vivo binding
  • Non-human primates