Skip to main content
Log in

Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats

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

Abstract

Rationale

Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.

Objectives

The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.

Methods

P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.

Results

Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.

Conclusions

Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.

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

Access this article

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ait-Daoud N, Wiesbeck GA, Bienkowski P, Li MD, Pfutzer SMV, Lesch OM, Johnson BA (2005) Comorbid alcohol and nicotine dependence: from bimolecular basis to clinical consequences. Alc: Clin Exp Res 29:1541–1549

    Article  CAS  Google Scholar 

  • Arneric SP, Holladay M, Williams M (2007) Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem Pharmacol 74:1092–1101

    Article  CAS  PubMed  Google Scholar 

  • Blomqvist O, Engel JA, Nissbrandt H, Soderpalm B (1993) The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine. Eur J Pharmacol 249:207–213

    Article  CAS  PubMed  Google Scholar 

  • Blomqvist O, Ericson M, Johnson DH, Engel JA, Soderpalm B (1996) Voluntary ethanol intake in the rat: effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment. Eur J Pharmacol 314:257–267

    Article  CAS  PubMed  Google Scholar 

  • Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, Scheibal D, Jou J, Allen V, Tiongson E, Chefer SI, Koren AO, Mukhin AG (2006) Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arc Gen Psychiat 63:907–915

    Article  CAS  Google Scholar 

  • Brody AL, Mandelkern MA, Olmstead RE, Allen-Martinez Z, Scheibal D, Abrama AL, Costello MR, Farahi J, Saxena S, Monterosso J, London ED (2009) Ventral striatum dopamine release in response to smoking a regular vs a denicotinized cigarette. Neuropsychopharmacology 34:282–289

    Article  CAS  PubMed  Google Scholar 

  • Collins AC (1990) Interactions of ethanol and nicotine at the receptor level. Recent Dev Alcohol 8:221–231

    CAS  PubMed  Google Scholar 

  • Cowen MS, Rezvani AH, Jarrott B, Lawrence AJ (1999) Ethanol consumption by fawn-hooded rats following abstinence: effects of naltrexone and changes in µ-opioid receptors density. Alc: Clin Exp Res 23:1008–1014

    CAS  Google Scholar 

  • Cucchiaro G, Xiao Y, Gonzalez-Sulser A, Kellar KJ (2008) Analgesic effects of sazetidine-A, a new nicotinic cholinergic drug. Anesthesiology 109:512–519

    Article  CAS  PubMed  Google Scholar 

  • DiChiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 8514:5274–5278

    Article  Google Scholar 

  • Ericson M, Blomqvist O, Engel JA, Söderpalm B (1998) Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine. Eur J Pharmcol 358:189–196

    Article  CAS  Google Scholar 

  • Ericson M, Löf E, Stomberg R, Söderpalm B (2009) The smoking cessation medication varenicline attenuates alcohol and nicotine interactions in the rat mesolimbic dopamine system. J Pharma Exp Ther 329:225–230

    Article  CAS  Google Scholar 

  • Farook JM, Lewis B, Gaddis JG, Littleton JM, Barron S (2009) Effects of mecamylamine on alcohol consumption and preference in male C57BL/6J mice. Pharmacology 83:379–384

    Article  CAS  PubMed  Google Scholar 

  • Fiore MC, Smith SS, Jorenby DE, Baker TB (1994) The effectiveness of the nicotine patch for smoking cessation—a meta-analysis. JAMA 271:1940–1947

    Article  CAS  PubMed  Google Scholar 

  • Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, Dorfman SF, Froelicher ES, Goldstein MG, Healton CG, Henderson PN, Heyman RB, Koh HK, Kottke TE, Lando HA, Mecklenburg RE, Mermelstein RJ, Mullen PD, Orleans CT, Robinson L, Stitzer ML, Tommasello AC, Villejo L, Wewers ME (2008) Clinical practice guideline: treating tobacco use and dependence: 2008 update. Department of Health and Human Services

  • Freedman R (2007) Exacerbation of schizophrenia by varenicline. Am J Psychiat 164:169

    Google Scholar 

  • Garbutt JC (2009) The state of pharmacotherapy for the treatment of alcohol dependence. J Subst Abuse Treat 36:15–23

    Google Scholar 

  • Gordon TL, Meehan SM, Schechter MD (1993) P and NP rats respond differently to the discriminative stimulus effects of nicotine. Pharmacol Biochem Behav 45:305–308

    Article  CAS  PubMed  Google Scholar 

  • Greenbaum L, Kanyas K, Karni O, Merbl Y, Olender T, Horowitz A, Yakir A, Lancet D, Ben-Asher E, Lerer B (2006) Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes. Mol Psychiatry 11:312–322

    Article  CAS  PubMed  Google Scholar 

  • Hendrickson LM, Zhao-Shea R, Tapper AR (2009) Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice. Psychopharmacology 204:563–572

    Article  CAS  PubMed  Google Scholar 

  • Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, KE KE, Billing CB, Gong J, Reeves KR, Group VPS (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  CAS  PubMed  Google Scholar 

  • Kamens HM, Phillips TJ (2008) A role for neuronal nicotinic acetylcholine receptors in ethanol-induced stimulation, but not cocaine- or methamphetamine-induced stimulation. Psychopharmacology 196:377–387

    Article  CAS  PubMed  Google Scholar 

  • Katz B, Thesleff S (1957) A study of the desensitization produced by acetylcholine at the motor end-plate. J Physiol 138:63–80

    CAS  PubMed  Google Scholar 

  • Kenna GA, Lomastro TL, Schiesl A, Leggio L, Swift RM (2009) Review of topiramate: an antiepileptic for the treatment of alcohol dependence. Current Drug Abuse Reviews 2:135–142

    Article  CAS  PubMed  Google Scholar 

  • Kranzler JH, Van Kirk J (2001) Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alc Clin Exp Res 25:1335–1341

    Article  CAS  Google Scholar 

  • Kuzmin A, Jerlhag E, Liljequist EJ (2009) Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior. Psychopharmacology 203:99–108

    Article  CAS  PubMed  Google Scholar 

  • Langley JH, Dickenson WL (1889) On the local paralysis of the peripheral ganglia and on the connexion of different classes of nerve fibers with them. Proc Royal Soc 46:423–431

    Article  Google Scholar 

  • Larsson A, Edström L, Svensson L, Söderpalm B, Engel JA (2005) Voluntary ethanol intake increases extracellular acetylcholine levels in the ventral tegmental area in the rat. Alcohol Alcohol 40:349–358

    CAS  PubMed  Google Scholar 

  • Lĕ AD, Corrigall WA, Harding JW, Juzytsch W, Li TK (2000) Involvement of nicotinic receptors in alcohol self-administration. Alcohol Clin Exp Res 24:155–163

    Article  PubMed  Google Scholar 

  • Lĕ AD, Wang A, Harding S, Juzytsch W, Shaham Y (2003) Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats. Psychopharmacology 168:216–221

    Article  PubMed  Google Scholar 

  • Lê AD, Li Z, Funk D, Shram M, Li TK, Shaham Y (2006) Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake. J Neurosci 26:1872–1879

    Article  PubMed  Google Scholar 

  • Levin ED, Westman EC, Stein RM, Carnahan E, Sanchez M, Herman S, Behm FM, Rose JE (1994) Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms and attenuates rewarding effects of smoking. J Clin Psychopharmacol 14:41–49

    Article  CAS  PubMed  Google Scholar 

  • Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells C, Hampton D, Petro A, Rose JE, Brown ML, Paige MA, McDowell BE, Kellar KJ (2010) Sazetidine-A, a selective α4β2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats. J Pharmacol Exp Ther 332:933–939

    Article  CAS  PubMed  Google Scholar 

  • Li TK, Lumeng L, Doolittle DP (1993) Selective breeding for alcohol preference and associated response. Behv Genet 23:163–170

    Article  CAS  Google Scholar 

  • Li TK, Volkow ND, Baler RD, Egli M (2007) The biological bases of nicotine and alcohol co-addiction. Biol Psychiatry 61:1–3

    Article  PubMed  Google Scholar 

  • Löf E, Olausson P, deBejczy A, Stomberg R, McIntosh JM, Taylor JR, Söderpalm B (2007) Nicotine acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology 195:333–343

    Article  PubMed  Google Scholar 

  • Mann K, Kiefer F, Spanagel R, Littleton J (2008) Acamprosate: recent findings and future research directions. Alc: Clin Exp Res 32:1105–1110

    Article  CAS  Google Scholar 

  • McKee SA, Harrison EL, O'Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM, Picciotto MR, Petrakis IL, Estevez N, Balchunas E (2009) Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 66:185–190

    Article  CAS  PubMed  Google Scholar 

  • Morstad AE, Kutscher EC, Kennedy WK, Carnahan RM (2008) Hypomania with agitation associated with varenicline use in bipolar II disorder. Ann Pharmacother 42:288

    Article  PubMed  Google Scholar 

  • Murphy JM, Stewart RB, Bell RL, Badia-Elder NE, Carr LG, McBride WJ, Lumeng L, Li TK (2002) Phenotypic and genotypic characterization of the Indiana University rat lines selectively bred for high and low alcohol preference. Behav Genet 312:363–388

    Article  Google Scholar 

  • Nisell M, Nomikos GG, Svensson TH (1994) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36–44

    Article  CAS  PubMed  Google Scholar 

  • O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B (1992) Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 49:881–887

    PubMed  Google Scholar 

  • Overstreet DH, Kampov-Polevoy AB, Rezvani AH, Braun C, Bartus RB, Crews F (1999) Suppression of alcohol intake by chronic naloxone treatment in P rats: tolerance development and elevation of opiate receptor binding. Alco: Clin Exp Res 23:1761–1771

    CAS  Google Scholar 

  • Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Changeux U, Maskos JP, Fratta W (2008) Crucial role of a4 and a6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28:12318–12327

    Article  CAS  PubMed  Google Scholar 

  • Potthoff AD, Elison G, Nelson L (1983) Ethanol intake increases during continuous administration of amphetamine and nicotine but not several other drugs. Pharmacol Biochem Behav 18:489–493

    Article  CAS  PubMed  Google Scholar 

  • Rezvani AH, Grady DR, Pucilowski O (1993) Nimodipine, a Ca2+ channel antagonist, attenuates alcohol preference in alcohol preferring rats. Drugs Dev 2:143–151

    CAS  Google Scholar 

  • Rezvani AH, Overstreet DH, Mason GA, Janowsky DS, Hamedi M, Jr C, Ying Y (2000) Combination pharmacotherapy: a mixture of small doses of naltrexone, fluoxetine, and a TRH analog reduces alcohol intake in three strains of alcohol preferring rats. Alcohol Alcohol 35:76–83

    CAS  PubMed  Google Scholar 

  • Rezvani AH, Overstreet DH, Levin ED, Rosenthal DI, Kordik CP, Reitz AB, Vaidya AH (2007) The effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) on alcohol intake in alcohol-preferring P rats: comparison with naltrexone. Alc: Clin Exp Res 31:57–63

    Article  CAS  Google Scholar 

  • Rezvani AH, Overstreet DH, Vaidya AH, Zhao B, Levin ED (2009) Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol preferring rats. Alc: Clin Exp Res 33:1366–1373

    Article  CAS  Google Scholar 

  • Rigbi A, Kanyas K, Yakir A, Greenbaum L, Pollak Y, Ben-Asher E, Lancet D, Kertzman S, Lerer B (2008) Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function. Genes Brain Behav 7:164–172

    Article  CAS  PubMed  Google Scholar 

  • Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, Lu Y, Mansbach RS, Mather RJ, Rovetti CC, Sands SB, Schaeffer E, Schulz DW, Tingley FD 3rd, Williams KE (2007) Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52:985–994

    Article  CAS  PubMed  Google Scholar 

  • Rose JE, Behm FM, Westman EC (1998) Nicotine–mecamylamine treatment for smoking cessation: the role of pre-cessation therapy. Exp Clin Psychopharmacology 6:331–343

    Article  CAS  Google Scholar 

  • Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Lessem HCJ, JM McQueen MB, Rhee SH, Ehringer MA (2008) The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 63:1039–1046

    Article  CAS  PubMed  Google Scholar 

  • Söderpalm B, Ericson M, Olausson P, Blomqvist O, Engel JA (2000) Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res 113:85–96

    Article  PubMed  Google Scholar 

  • Söderpalm B, Lof E, Ericson M (2009) Mechanistic studies of ethanol's interaction with the mesolimbic dopamine reward system. Pharmacopsychiatry 42(Suppl 1):S87–S94

    Article  PubMed  Google Scholar 

  • Steensland P, Simms JA, Holgate J, Richards JK, Barlett SE (2007) Varenicline, an α4β2 nicotinic acetylcholine receptors partial agonist, selectively decreases ethanol consumption and seeking. PNAS 104:12518–12523

    Article  CAS  PubMed  Google Scholar 

  • Tizabi Y, Bai L, Copeland RL Jr, Taylor RE (2007) Combined effects of systemic alcohol and nicotine on dopamine release in the nucleus accumbens shell. Alcohol Alcohol 42:413–416

    CAS  PubMed  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004) Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 9:557–569

    Article  CAS  PubMed  Google Scholar 

  • Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258

    CAS  PubMed  Google Scholar 

  • Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, Kellar KJ (2006) Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. Mol Pharmacol 70:1454–1460

    Article  CAS  PubMed  Google Scholar 

  • Xiao Y, Yasuda RP, Sahibzada N, Horton L, DiPietro JR, Iwueze AF, Paige MA, McDowell BE, Brown ML, Wolfe BB, Kellar KJ (2008) Pharmacological properties of sazetidine-A, a selective ligand of α4β2 nicotinic acetylcholine receptors, in Proceedings of the 38 Annual Meeting of the Society for Neuroscience, Washington DC.

  • Yasuda RP, Xiao Y, Sahibzada N, McDowell BE, Paige MA, Brown ML, Wolfe BB, Kellar KJ (2009) Desensitization and time course of recovery of α4β2 nicotinic receptors after brief exposure to agonists and partial agonists, in Proceedings of the 39 Annual Meeting of the Society for Neuroscience, Chicago, IL.

Download references

Acknowledgements

The authors thank Alan P. Kozikowski, Sheela K. Chellappan, Krishna Mohan Bajjuri, for synthesizing some of the sazetidine-A samples used in this study. Georgetown University holds patent rights for sazetidine-A, and Drs. Xiao and Kellar are two of the inventors on this patent. This research was supported by an unrestricted grant from Philip Morris USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amir H. Rezvani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rezvani, A.H., Slade, S., Wells, C. et al. Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats. Psychopharmacology 211, 161–174 (2010). https://doi.org/10.1007/s00213-010-1878-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-1878-8

Keywords

Navigation