Skip to main content

Advertisement

SpringerLink
Log in

Positive allosteric modulation of α4β2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) plays a central role in the mediation of nicotine reinforcement. Positive allosteric modulators (PAMs) at α4β2 nAChRs facilitate the intrinsic efficiency of these receptors, although they do not directly activate the receptors. α4β2 PAMs are hypothesized to reduce nicotine self-administration in subjects engaged in routine nicotine consumption. The present study tested this hypothesis using a rat model of nicotine self-administration.

Methods

Male Sprague–Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine (0.03 mg/kg per infusion, free base) on a fixed-ratio 5 schedule. The effects of the α4β2 PAM desformylflustrabromine (dFBr), α4β2 agonist 5-iodo-A-85380, and acetylcholinesterase inhibitor galantamine on nicotine intake were examined. The ability of dFBr and 5-iodo-A-85380 to substitute for nicotine was also assessed.

Results

dFBr and 5-iodo-A-85380 dose-dependently reduced nicotine self-administration without changing lever responses for food. Galantamine decreased the self-administration of nicotine and food at high doses. Unlike 5-iodo-A-85380, dFBr failed to substitute for nicotine in supporting self-administration behavior.

Conclusions

These results demonstrated the effectiveness of dFBr in reducing nicotine intake and the inability of dFBr to support self-administration behavior. These findings suggest that positive allosteric modulation of α4β2 nAChRs may be a promising target for the treatment of nicotine addiction. Moreover, α4β2 PAMs, in contrast to agonist medications, may have clinical advantages because they may have little liability for abuse because of their lack of reinforcing actions on their own.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ator NA, Griffiths RR (2003) Principles of drug abuse liability assessment in laboratory animals. Drug Alcohol Depend 70:S55–S72

    Article  PubMed  CAS  Google Scholar 

  • Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB Jr, Gong J, Williams KE, Reeves KR (2008) Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised, open-label trial. Thorax 63:717–724

    Article  PubMed  Google Scholar 

  • Baettig K, Martin JR, Classen W (1980) Nicotine and amphetamine: differential tolerance and no cross-tolerance for ingestive effects. Pharmacol Biochem Behav 12:107–111

    Article  PubMed  CAS  Google Scholar 

  • Bertrand D, Gopalakrishnan M (2007) Allosteric modulation of nicotinic acetylcholine receptors. Biochem Pharmacol 74:1155–1163

    Article  PubMed  CAS  Google Scholar 

  • Besson M, David V, Baudonnat M, Cazala P, Guilloux JP, Reperant C, Cloez-Tayarani I, Changeux JP, Gardier AM, Granon S (2012) Alpha7-nicotinic receptors modulate nicotine-induced reinforcement and extracellular dopamine outflow in the mesolimbic system in mice. Psychopharmacology (Berl) 220:1–14

    Article  CAS  Google Scholar 

  • Brunzell DH (2012) Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype. Nicotine Tob Res 14:1258–1269

    Article  PubMed  CAS  Google Scholar 

  • Brunzell DH, McIntosh JM (2012) Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia. Neuropsychopharmacology 37:1134–1143

    Article  PubMed  CAS  Google Scholar 

  • Cahill K, Stead LF, Lancaster T (2011) Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2:CD006103

    PubMed  Google Scholar 

  • CDC (2008) Cigarette smoking in adults—United States, 2007. MMWR Weekly 57(45):1121–1126

    Google Scholar 

  • Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD 3rd, O’Neill BT (2005) Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48:3474–3477

    Article  PubMed  CAS  Google Scholar 

  • Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284

    Article  PubMed  CAS  Google Scholar 

  • Ehlert FJ (2005) Analysis of allosterism in functional assays. J Pharmacol Exp Ther 315:740–754

    Article  PubMed  CAS  Google Scholar 

  • Exley R, Cragg SJ (2008) Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharmacol 153(Suppl 1):S283–S297

    PubMed  CAS  Google Scholar 

  • Fant RV, Buchhalter AR, Buchman AC, Henningfield JE (2009) Pharmacotherapy for tobacco dependence. Handb Exp Pharmacol 192:487–510

    Article  PubMed  CAS  Google Scholar 

  • Fryer JD, Lukas RJ (1999) Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 288:88–92

    PubMed  CAS  Google Scholar 

  • Goh CW, Aw CC, Lee JH, Chen CP, Browne ER (2011) Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats. Drug Metab Dispos 39:402–411

    Article  PubMed  CAS  Google Scholar 

  • Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR (2006) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296:47–55

    Article  PubMed  CAS  Google Scholar 

  • Gozzi A, Schwarz A, Reese T, Bertani S, Crestan V, Bifone A (2006) Region-specific effects of nicotine on brain activity: a pharmacological MRI study in the drug-naive rat. Neuropsychopharmacology 31:1690–1703

    Article  PubMed  CAS  Google Scholar 

  • Grabus SD, Martin BR, Brown SE, Damaj MI (2006) Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists. Psychopharmacology (Berl) 184:456–463

    Article  CAS  Google Scholar 

  • Grasing K, He S, Yang Y (2008) Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats. Psychopharmacology (Berl) 196:133–142

    Article  CAS  Google Scholar 

  • Grottick AJ, Trube G, Corrigall WA, Huwyler J, Malherbe P, Wyler R, Higgins GA (2000) Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine. J Pharmacol Exp Ther 294:1112–1119

    PubMed  CAS  Google Scholar 

  • Hopkins TJ, Rupprecht LE, Hayes MR, Blendy JA, Schmidt HD (2012) Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats. Neuropsychopharmacology 37:2310–2321

    Article  PubMed  CAS  Google Scholar 

  • Houtsmuller EJ, Fant RV, Eissenberg TE, Henningfield JE, Stitzer ML (2002) Flavor improvement does not increase abuse liability of nicotine chewing gum. Pharmacol Biochem Behav 72:559–568

    Article  PubMed  CAS  Google Scholar 

  • Hughes JR (1989) Dependence potential and abuse liability of nicotine replacement therapies. Biomed Pharmacother 43:11–17

    Article  PubMed  CAS  Google Scholar 

  • Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006) Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63

    Article  PubMed  CAS  Google Scholar 

  • Kim JS, Padnya A, Weltzin M, Edmonds BW, Schulte MK, Glennon RA (2007) Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator. Bioorg Med Chem Lett 17:4855–4860

    Article  PubMed  CAS  Google Scholar 

  • Li SX, Perry KW, Wong DT (2002) Influence of fluoxetine on the ability of bupropion to modulate extracellular dopamine and norepinephrine concentrations in three mesocorticolimbic areas of rats. Neuropharmacology 42:181–190

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Caggiula AR, Palmatier MI, Donny EC, Sved AF (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology (Berl) 196:365–375

    Article  CAS  Google Scholar 

  • Liu X, Koren AO, Yee SK, Pechnick RN, Poland RE, London ED (2003) Self-administration of 5-iodo-A-85380, a beta2-selective nicotinic receptor ligand, by operantly trained rats. Neuroreport 14:1503–1505

    Article  PubMed  CAS  Google Scholar 

  • Lysek N, Rachor E, Lindel T (2002) Isolation and structure elucidation of deformylflustrabromine from the North Sea bryozoan Flustra foliacea. Z Naturforsch C 57:1056–1061

    PubMed  CAS  Google Scholar 

  • Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, Zerlin M (2001) Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease. Biol Psychiatry 49:279–288

    Article  PubMed  CAS  Google Scholar 

  • Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque EX (2000) Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Behav Brain Res 113:199–206

    Article  PubMed  CAS  Google Scholar 

  • Mansbach RS, Chambers LK, Rovetti CC (2000) Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine. Psychopharmacology (Berl) 148:234–242

    Article  CAS  Google Scholar 

  • Markou A, Paterson NE (2001) The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res 3:361–373

    Article  PubMed  CAS  Google Scholar 

  • Marx CE, McIntosh E, Wilson WH, McEvoy JP (2000) Mecamylamine increases cigarette smoking in psychiatric patients. J Clin Psychopharmacol 20:706–707

    Article  PubMed  CAS  Google Scholar 

  • McKee SA, Weinberger AH, Harrison EL, Coppola S, George TP (2009) Effects of the nicotinic receptor antagonist mecamylamine on ad-lib smoking behavior, topography, and nicotine levels in smokers with and without schizophrenia: a preliminary study. Schizophr Res 115:317–324

    Article  PubMed  Google Scholar 

  • Mineur YS, Abizaid A, Rao Y, Salas R, DiLeone RJ, Gundisch D, Diano S, De Biasi M, Horvath TL, Gao XB, Picciotto MR (2011) Nicotine decreases food intake through activation of POMC neurons. Science 332:1330–1332

    Article  PubMed  CAS  Google Scholar 

  • Mineur YS, Picciotto MR (2008) Genetics of nicotinic acetylcholine receptors: relevance to nicotine addiction. Biochem Pharmacol 75:323–333

    Article  PubMed  CAS  Google Scholar 

  • Moser P, Wolinsky T, Castagne V, Duxon M (2011) Current approaches and issues in non-clinical evaluation of abuse and dependence. J Pharmacol Toxicol Methods 63:160–167

    Article  PubMed  CAS  Google Scholar 

  • Mukhin AG, Gundisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS, Chambers J, Vaupel DB, King SL, Picciotto MR, Innis RB, London ED (2000) 5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors. Mol Pharmacol 57:642–649

    PubMed  CAS  Google Scholar 

  • Nemeth-Coslett R, Henningfield JE, O’Keeffe MK, Griffiths RR (1986) Effects of mecamylamine on human cigarette smoking and subjective ratings. Psychopharmacology (Berl) 88:420–425

    Article  CAS  Google Scholar 

  • Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1989) Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis. Neuropsychopharmacology 2:273–279

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Kenny PJ (2012) Molecular mechanisms underlying behaviors related to nicotine addiction. Cold Spring Harb Perspect Med 3(1):a01211

    Google Scholar 

  • Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Changeux JP, Maskos U, Fratta W (2008) Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28:12318–12327

    Article  PubMed  CAS  Google Scholar 

  • Rose JE, Behm FM, Westman EC (2001) Acute effects of nicotine and mecamylamine on tobacco withdrawal symptoms, cigarette reward and ad lib smoking. Pharmacol Biochem Behav 68:187–197

    Article  PubMed  CAS  Google Scholar 

  • Sala F, Mulet J, Reddy KP, Bernal JA, Wikman P, Valor LM, Peters L, Konig GM, Criado M, Sala S (2005) Potentiation of human alpha4beta2 neuronal nicotinic receptors by a Flustra foliacea metabolite. Neurosci Lett 373:144–149

    Article  PubMed  CAS  Google Scholar 

  • Santos MD, Alkondon M, Pereira EF, Aracava Y, Eisenberg HM, Maelicke A, Albuquerque EX (2002) The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system. Mol Pharmacol 61:1222–1234

    Article  PubMed  CAS  Google Scholar 

  • Sargent PB (1993) The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci 16:403–443

    Article  PubMed  CAS  Google Scholar 

  • Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX, Maelicke A (1996) Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49:1–6

    PubMed  CAS  Google Scholar 

  • Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327

    PubMed  CAS  Google Scholar 

  • Stolerman IP, Chamberlain S, Bizarro L, Fernandes C, Schalkwyk L (2004) The role of nicotinic receptor alpha 7 subunits in nicotine discrimination. Neuropharmacology 46:363–371

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Thomsen T, Kaden B, Fischer JP, Bickel U, Barz H, Gusztony G, Cervos-Navarro J, Kewitz H (1991) Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galanthamine, physostigmine and tacrine. Eur J Clin Chem Clin Biochem 29:487–492

    PubMed  CAS  Google Scholar 

  • Toll L, Zaveri NT, Polgar WE, Jiang F, Khroyan TV, Zhou W, Xie XS, Stauber GB, Costello MR, Leslie FM (2012) AT-1001: a high affinity and selective alpha3beta4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats. Neuropsychopharmacology 37:1367–1376

    Article  PubMed  CAS  Google Scholar 

  • Tuesta LM, Fowler CD, Kenny PJ (2011) Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior. Biochem Pharmacol 82:984–995

    Article  PubMed  CAS  Google Scholar 

  • Ueda M, Iida Y, Mukai T, Mamede M, Ishizu K, Ogawa M, Magata Y, Konishi J, Saji H (2004) 5-[123I]Iodo-A-85380: assessment of pharmacological safety, radiation dosimetry and SPECT imaging of brain nicotinic receptors in healthy human subjects. Ann Nucl Med 18:337–344

    Article  PubMed  CAS  Google Scholar 

  • van Beijsterveldt L, Geerts R, Verhaeghe T, Willems B, Bode W, Lavrijsen K, Meuldermans W (2004) Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat. Arzneimittelforschung 54:85–94

    PubMed  Google Scholar 

  • van Haaren F, Anderson KG, Haworth SC, Kem WR (1999) GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue. Pharmacol Biochem Behav 64:439–444

    Article  PubMed  Google Scholar 

  • Vieyra-Reyes P, Picciotto MR, Mineur YS (2008) Voluntary oral nicotine intake in mice down-regulates GluR2 but does not modulate depression-like behaviors. Neurosci Lett 434:18–22

    Article  PubMed  CAS  Google Scholar 

  • Walters CL, Brown S, Changeux JP, Martin B, Damaj MI (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacology (Berl) 184:339–344

    Article  CAS  Google Scholar 

  • Weltzin MM, Schulte MK (2010) Pharmacological characterization of the allosteric modulator desformylflustrabromine and its interaction with alpha4beta2 neuronal nicotinic acetylcholine receptor orthosteric ligands. J Pharmacol Exp Ther 334:917–926

    Article  PubMed  CAS  Google Scholar 

  • West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A (2000) A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology (Berl) 149:198–202

    Article  CAS  Google Scholar 

  • Wonnacott S, Sidhpura N, Balfour DJ (2005) Nicotine: from molecular mechanisms to behaviour. Curr Opin Pharmacol 5:53–59

    Article  PubMed  CAS  Google Scholar 

  • Woodruff-Pak DS, Vogel RW 3rd, Wenk GL (2001) Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci U S A 98:2089–2094

    Article  PubMed  CAS  Google Scholar 

  • Zoli M, Lena C, Picciotto MR, Changeux JP (1998) Identification of four classes of brain nicotinic receptors using beta2 mutant mice. J Neurosci 18:4461–4472

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grant DA017288 from the National Institute on Drug Abuse and startup funds from the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center. The author would like to thank Courtney Jernigan, Laura Beloate, Ramachandram Avusula, Treniea Tolliver, and Trisha Patel for their excellent technical assistance and Dr. Rodney Baker and Mrs. Christine Purser at the HPLC/Mass Spectrometry Analytical Core, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, for their great effort for the measurement of dFBr in blood and cerebrospinal fluid samples.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA

    Xiu Liu

Authors
  1. Xiu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiu Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, X. Positive allosteric modulation of α4β2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration. Psychopharmacology 230, 203–213 (2013). https://doi.org/10.1007/s00213-013-3145-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3145-2

Keywords

Search

Navigation