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The role of varenicline on alcohol-primed self-administration and seeking behavior in rats

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Abstract

Rationale

Varenicline, a smoking-cessation agent, may be useful in treating alcohol use disorders. An important consideration when studying factors that influence drinking/relapse is influence of the pharmacological effects of alcohol on these behaviors. Pre-exposure to alcohol (priming) can increase craving, drinking, and seeking behaviors.

Objectives

The primary goal of this work was to determine the effects of varenicline on alcohol-primed self-administration and seeking behavior in male Long-Evans rats.

Methods

First, we assessed whether varenicline (0, 0.3, 1, 3 mg/kg, IP) has alcohol-like discriminative stimulus effects and whether varenicline alters sensitivity to alcohol in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, animals trained to self-administer alcohol underwent assessments to test the effects of: (i) varenicline (0, 0.3, 1, 3 mg/kg, IP) on self-administration, (ii) alcohol priming (0, 0.3, 1 g/kg, IG) on self-administration and seeking behavior, and (iii) varenicline (1 mg/kg) in combination with alcohol priming (1 g/kg) on these behaviors.

Results

Varenicline did not substitute for alcohol but disrupted the expression of sensitivity to alcohol. Varenicline decreased self-administration but only at a motor-impairing dose (3 mg/kg). Alcohol priming decreased self-administration and seeking behavior. Varenicline (1 mg/kg) blocked this effect under self-administration conditions, but not seeking conditions, which effectively resulted in increased alcohol intake.

Conclusions

These findings suggest the importance of further behavioral and mechanistic studies to evaluate the use of varenicline in treating alcohol use disorders and its potential impact on drinking patterns in smokers using varenicline as a smoking-cessation aid.

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References

  • Anker JJ, Carroll ME (2010) Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology (Berl) 208:211–222

    Article  CAS  Google Scholar 

  • Besheer J, Grondin JJ, Salling MC, Spanos M, Stevenson RA, Hodge CW (2009) Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci 29:9582–9591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Besheer J, Grondin JJ, Cannady R, Sharko AC, Faccidomo S, Hodge CW (2010) Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake. Biol Psychiatry 67:812–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Besheer J, Fisher KR, Cannady R, Grondin JJ, Hodge CW (2012) Intra-amygdala inhibition of ERK(1/2) potentiates the discriminative stimulus effects of alcohol. Behav Brain Res 228:398–405

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Besheer J, Fisher KR, Lindsay TG, Cannady R (2013) Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone. Neuropharmacology 72:139–147

    Article  CAS  PubMed  Google Scholar 

  • Besheer J, Fisher KR, Jaramillo AA, Frisbee S, Cannady R (2014) Stress hormone exposure reduces mGluR5 expression in the nucleus accumbens: functional implications for interoceptive sensitivity to alcohol. Neuropsychopharmacology 39:2376–2386

    Article  CAS  PubMed  Google Scholar 

  • Bigelow GE, Griffiths RR, Liebson IA (1977) Pharmacological influences upon human ethanol self-administration. Adv Exp Med Biol 85B:523–538

    Article  CAS  PubMed  Google Scholar 

  • Cahill K, Stead LF, Lancaster T (2012) Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 4, CD006103

    PubMed  Google Scholar 

  • Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW (2013) Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol 18:54–65

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chatterjee S, Bartlett SE (2010) Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders. CNS Neurol Disord Drug Targets 9:60–76

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Childs E, Roche DJ, King AC, de Wit H (2012) Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements. Alcohol Clin Exp Res 36:906–914

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chutuape MA, de Wit H (1994) Relationship between subjective effects and drug preferences: ethanol and diazepam. Drug Alcohol Depend 34:243–251

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Colpaert FC (1987) Drug discrimination in behavioral toxicology. Zentralbl Bakteriol Mikrobiol Hyg B 185:48–51

    CAS  PubMed  Google Scholar 

  • Colpaert FC, Niemegeers CJ, Janssen PA (1979) Discriminative stimulus properties of cocaine: neuropharmacological characteristics as derived from stimulus generalization experiments. Pharmacol Biochem Behav 10:535–546

    Article  CAS  PubMed  Google Scholar 

  • Czachowski CL, Legg BH, Samson HH (2003) Assessment of sucrose and ethanol reinforcement: the across-session breakpoint procedure. Physiol Behav 78:51–59

    Article  CAS  PubMed  Google Scholar 

  • Czachowski CL, Prutzman S, DeLory MJ (2006) Volume and dose effects of experimenter- administered ethanol preloads on ethanol seeking and self-administration. Alcohol 40:35–40

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dani JA, Harris RA (2005) Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci 8:1465–1470

    Article  CAS  PubMed  Google Scholar 

  • de Wit H, Chutuape MA (1993) Increased ethanol choice in social drinkers following ethanol preload. Behav Pharmacol 4:29–36

    PubMed  Google Scholar 

  • Desai RI, Bergman J (2014) Methamphetamine-like discriminative-stimulus effects of nicotinic agonists. J Pharmacol Exp Ther 348:478–488

    Article  PubMed Central  PubMed  Google Scholar 

  • DiChiara TJ, Reinhart PH (1995) Distinct effects of Ca2+ and voltage on the activation and deactivation of cloned Ca(2+)-activated K+ channels. J Physiol 489(Pt 2):403–418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Erwin BL, Slaton RM (2014) Varenicline in the treatment of alcohol use disorders. Ann Pharmacother 48:1445–1455

    Article  PubMed  Google Scholar 

  • Falk DE, Yi HY, Hiller-Sturmhofel S (2006) An epidemiologic analysis of co-occurring alcohol and tobacco use and disorders: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. Alcohol Res Health 29:162–171

    PubMed  Google Scholar 

  • Fattore L, Spano MS, Cossu G, Deiana S, Fratta W (2003) Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. Eur J Neurosci 17:1723–1726

    Article  CAS  PubMed  Google Scholar 

  • Feduccia AA, Simms JA, Mill D, Yi HY, Bartlett SE (2014) Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens. Br J Pharmacol 171:3420–3431

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fucito LM, Toll BA, Wu R, Romano DM, Tek E, O'Malley SS (2011) A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology (Berl) 215:655–663

    Article  CAS  Google Scholar 

  • Gass JT, Olive MF (2007) Reinstatement of ethanol-seeking behavior following intravenous self-administration in Wistar rats. Alcohol Clin Exp Res 31:1441–1445

    Article  CAS  PubMed  Google Scholar 

  • Gerber GJ, Stretch R (1975) Drug-induced reinstatement of extinguished self-administration behavior in monkeys. Pharmacol Biochem Behav 3:1055–1061

    Article  CAS  PubMed  Google Scholar 

  • Ginsburg BC, Lamb RJ (2013) Effects of varenicline on ethanol- and food-maintained responding in a concurrent access procedure. Alcohol Clin Exp Res 37:1228–1233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ginsburg BC, Lamb RJ (2014) Relative potency of varenicline or fluvoxamine to reduce responding for ethanol versus food depends on the presence or absence of concurrently earned food. Alcohol Clin Exp Res 38:860–870

    Article  CAS  PubMed  Google Scholar 

  • Grant BF (1998) Age at smoking onset and its association with alcohol consumption and DSM-IV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 10:59–73

    Article  CAS  PubMed  Google Scholar 

  • Hendrickson LM, Zhao-Shea R, Pang X, Gardner PD, Tapper AR (2010) Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption. J Neurosci 30:10169–10176

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hobbs M, Remington B, Glautier S (2005) Dissociation of wanting and liking for alcohol in humans: a test of the incentive-sensitisation theory. Psychopharmacology (Berl) 178:493–499

    Article  CAS  Google Scholar 

  • Hodgson R, Rankin H, Stockwell T (1979) Alcohol dependence and the priming effect. Behav Res Ther 17:379–387

    Article  CAS  PubMed  Google Scholar 

  • Jackson A, Duka T, Stephens DN (2003) Effects of alcohol and lorazepam during extinction of alcohol self-administration in rats. J Psychopharmacol 17:293–299

    Article  CAS  PubMed  Google Scholar 

  • Kaminski BJ, Weerts EM (2014) The effects of varenicline on alcohol seeking and self-administration in baboons. Alcohol Clin Exp Res 38:376–383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kirk JM, de Wit H (2000) Individual differences in the priming effect of ethanol in social drinkers. J Stud Alcohol 61:64–71

    Article  CAS  PubMed  Google Scholar 

  • Le AD, Quan B, Juzytch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology (Berl) 135:169–174

    Article  CAS  Google Scholar 

  • Le AD, Poulos CX, Harding S, Watchus J, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21:435–444

    Article  CAS  PubMed  Google Scholar 

  • LeSage MG, Shelley D, Ross JT, Carroll FI, Corrigall WA (2009) Effects of the nicotinic receptor partial agonists varenicline and cytisine on the discriminative stimulus effects of nicotine in rats. Pharmacol Biochem Behav 91:461–467

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liang J, Olsen RW (2014) Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors. Acta Pharmacol Sin 35:981–993

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Litten RZ, Ryan ML, Fertig JB, Falk DE, Johnson B, Dunn KE, Green AI, Pettinati HM, Ciraulo DA, Sarid-Segal O, Kampman K, Brunette MF, Strain EC, Tiouririne NA, Ransom J, Scott C, Stout R (2013) A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med 7:277–286

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ludwig AM, Wikler A (1974) “Craving” and relapse to drink. Q J Stud Alcohol 35:108–130

    Google Scholar 

  • McKee SA, Falba T, O'Malley SS, Sindelar J, O'Connor PG (2007) Smoking status as a clinical indicator for alcohol misuse in US adults. Arch Intern Med 167:716–721

    Article  PubMed Central  PubMed  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 Central  PubMed  Google Scholar 

  • Mitchell JM, Teague CH, Kayser AS, Bartlett SE, Fields HL (2012) Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl) 223:299–306

    Article  CAS  Google Scholar 

  • Panlilio LV, Hogarth L, Shoaib M (2014) Concurrent access to nicotine and sucrose in rats. Psychopharmacology (Berl)

  • Rollema H, Hajos M, Seymour PA, Kozak R, Majchrzak MJ, Guanowsky V, Horner WE, Chapin DS, Hoffmann WE, Johnson DE, McLean S, Freeman J, Williams KE (2009) Preclinical pharmacology of the alpha4beta2 nAChR partial agonist varenicline related to effects on reward, mood and cognition. Biochem Pharmacol 78:813–824

    Article  CAS  PubMed  Google Scholar 

  • Samson HH, Chappell A (2002) Reinstatement of ethanol seeking responding after ethanol self-administration. Alcohol 26:95–101

    Article  CAS  PubMed  Google Scholar 

  • Samson HH, Czachowski CL (2003) Behavioral measures of alcohol self-administration and intake control: rodent models. Int Rev Neurobiol 54:107–143

    Article  PubMed  Google Scholar 

  • Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE (2007) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A 104:12518–12523

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stolerman I (1992) Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 13:170–176

    Article  CAS  PubMed  Google Scholar 

  • Stretch R, Gerber GJ (1973) Drug-induced reinstatement of amphetamine self-administration behaviour in monkeys. Can J Psychol 27:168–177

    Article  CAS  PubMed  Google Scholar 

  • Vosler PS, Bombace JC, Kosten TA (2001) A discriminative two-lever test of dizocilpine's ability to reinstate ethanol-seeking behavior. Life Sci 69:591–598

    Article  CAS  PubMed  Google Scholar 

  • Wouda JA, Riga D, De Vries W, Stegeman M, van Mourik Y, Schetters D, Schoffelmeer AN, Pattij T, De Vries TJ (2011) Varenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control. Psychopharmacology (Berl) 216:267–277

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported, in part, by funds from the National Institutes of Health AA019682 (JB) and the Bowles Center for Alcohol Studies.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Thurston-Bowles Building; CB#7178, Chapel Hill, NC, 27599, USA

    Patrick A. Randall, Anel A. Jaramillo, Suzanne Frisbee & Joyce Besheer

  2. Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7178, USA

    Anel A. Jaramillo & Joyce Besheer

  3. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7178, USA

    Joyce Besheer

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  1. Patrick A. Randall
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  2. Anel A. Jaramillo
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  3. Suzanne Frisbee
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  4. Joyce Besheer
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Correspondence to Joyce Besheer.

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Randall, P.A., Jaramillo, A.A., Frisbee, S. et al. The role of varenicline on alcohol-primed self-administration and seeking behavior in rats. Psychopharmacology 232, 2443–2454 (2015). https://doi.org/10.1007/s00213-015-3878-1

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  • DOI: https://doi.org/10.1007/s00213-015-3878-1

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