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Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse

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Abstract

Rationale and objectives

Alcohol and nicotine are often taken together. In humans, intake of nicotine, via smoked tobacco, increases alcohol drinking, and alcohol increases smoking. Chronic nicotine treatment increases alcohol self-administration (SA) in laboratory animals; the reverse relationship is less clear. Most animal work modeling this has used passive administration, which lacks relevance to human co-abuse. Here, we describe a model based on sequential operant SA of alcohol and nicotine.

Methods

Animals are first trained on alcohol SA (0.19 ml of 12 % alcohol (w/v)/delivery) and then receive separate alcohol (8 %, w/v) and nicotine (15 μg/kg/infusion) SA sessions on the same day (“daily dual access”). Animals then receive access to alcohol and then to nicotine (or in the reverse order) in alternating 5-min periods in 2-h sessions (“alternating access”). We then determine if alternating access modifies the effects of naltrexone on responding for alcohol and nicotine.

Results

We found that with daily dual access, nicotine significantly increased alcohol SA when alcohol access occurred prior to nicotine access and that nicotine SA significantly decreased when the alcohol SA session preceded it. During alternating access, nicotine also significantly increased alcohol intake. Naltrexone (0.3 or 1 mg/kg) significantly reduced alcohol SA during these alternating access sessions in animals that also received nicotine SA, but had minimal effects on animals receiving alcohol SA alone. Naltrexone did not affect nicotine SA under any condition.

Conclusions

This sequential access procedure effectively models the effects of nicotine on alcohol intake noted in humans.

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References

  • Acheson A, Mahler SV, Chi H, de Wit H (2006) Differential effects of nicotine on alcohol consumption in men and women. Psychopharmacology (Berl) 186:54–63

    Article  CAS  Google Scholar 

  • Barrett SP, Tichauer M, Leyton M, Pihl RO (2006) Nicotine increases alcohol self-administration in non-dependent male smokers. Drug Alcohol Depend 81:197–204

    Article  PubMed  CAS  Google Scholar 

  • Bienkowski P, Kostowski W, Koros E (1999) Ethanol-reinforced behaviour in the rat: effects of naltrexone. Eur J Pharmacol 374:321–327

    Article  PubMed  CAS  Google Scholar 

  • Bito-Onon JJ, Simms JA, Chatterjee S, Holgate J, Bartlett SE (2011) Varenicline, a partial agonist at neuronal nicotinic acetylcholine receptors, reduces nicotine-induced increases in 20 % ethanol operant self-administration in Sprague-Dawley rats. Addict Biol 16:440–449

    Article  PubMed  CAS  PubMed Central  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. Arch Gen Psychiatry 63:907–915

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chen WJ, Parnell SE, West JR (2001) Nicotine decreases blood alcohol concentration in neonatal rats. Alcohol Clin Exp Res 25:1072–1077

    Article  PubMed  CAS  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 

  • Corrigall WA, Coen KM (1991) Opiate antagonists reduce cocaine but not nicotine self-administration. Psychopharmacology (Berl) 104:167–170

    Article  CAS  Google Scholar 

  • Corrigall WA, Herling S, Coen KM (1988) Evidence for opioid mechanisms in the behavioral effects of nicotine. Psychopharmacology (Berl) 96:29–35

    Article  CAS  Google Scholar 

  • Czachowski CL, Delory MJ (2009) Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats. Psychopharmacology (Berl) 204:335–348

    Article  CAS  Google Scholar 

  • Czachowski CL, Samson HH, Denning CE (1999) Independent ethanol- and sucrose-maintained responding on a multiple schedule of reinforcement. Alcohol Clin Exp Res 23:398–403

    Article  PubMed  CAS  Google Scholar 

  • Damsma G, Day J, Fibiger HC (1989) Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur J Pharmacol 168:363–268

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Dhaher R, Toalston JE, Hauser SR, Bell RL, McKinzie DL, McBride WJ, Rodd ZA (2012) Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Alcohol 46:17–27

    Article  PubMed  CAS  Google Scholar 

  • Dohrman DP, Reiter CK (2003) Ethanol modulates nicotine-induced upregulation of nAChRs. Brain Res 975:90–98

    Article  PubMed  CAS  Google Scholar 

  • Doyon WM, Dong Y, Ostroumov A, Thomas AM, Zhang TA, Dani JA (2013) Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones. Neuron 79:530–540

    Article  PubMed  CAS  PubMed Central  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 

  • Feyerabend C, Ings RM, Russel MA (1985) Nicotine pharmacokinetics and its application to intake from smoking. Br J Clin Pharmacol 19:239–247

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fucito LM, Park A, Gulliver SB, Mattson ME, Gueorguieva RV, O'Malley SS (2012) Cigarette smoking predicts differential benefit from naltrexone for alcohol dependence. Biol Psychiatry 72:832–838

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Funk D, Marinelli PW, Le AD (2006) Biological processes underlying co-use of alcohol and nicotine: neuronal mechanisms, cross-tolerance, and genetic factors. Alcohol Res Health 29:186–192

    PubMed  Google Scholar 

  • Galeote L, Kieffer BL, Maldonado R, Berrendero F (2006) Mu-opioid receptors are involved in the tolerance to nicotine antinociception. J Neurochem 97:416–423

    Article  PubMed  CAS  Google Scholar 

  • Giardino WJ, Ryabinin AE (2013) CRF1 receptor signaling regulates food and fluid intake in the drinking-in-the-dark model of binge alcohol consumption. Alcohol Clin Exp Res 37:1161–1170

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Glautier S, Clements K, White JA, Taylor C, Stolerman IP (1996) Alcohol and the reward value of cigarette smoking. Behav Pharmacol 7:144–154

    Article  PubMed  CAS  Google Scholar 

  • Hauser SR, Getachew B, Oster SM, Dhaher R, Ding ZM, Bell RL, McBride WJ, Rodd ZA (2012) Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner. Alcohol Clin Exp Res 36:43–54

    Article  PubMed  CAS  Google Scholar 

  • Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 111:855–876

    Article  PubMed  CAS  Google Scholar 

  • Hisaoka M, Levy G (1985) Kinetics of drug action in disease states XI: effect of nicotine on the pharmacodynamics and pharmacokinetics of phenobarbital and ethanol in rats. J Pharm Sci 74:412–415

    Article  PubMed  CAS  Google Scholar 

  • Hyytia P, Kiianmaa K (2001) Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats. Alcohol Clin Exp Res 25:25–33

    Article  PubMed  CAS  Google Scholar 

  • Kandel D, Chen K, Warner LA, Kessler RC, Grant B (1997) Prevalence and demographic correlates of symptoms of last year dependence on alcohol, nicotine, marijuana and cocaine in the U.S. population. Drug Alcohol Depend 44:11–29

    Article  PubMed  CAS  Google Scholar 

  • Kim SG, Stromberg MF, Kim MJ, Volpicelli JR, Park JM (2000) The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice. Alcohol 22:85–90

    Article  PubMed  CAS  Google Scholar 

  • King AC, Meyer PJ (2000) Naltrexone alteration of acute smoking response in nicotine-dependent subjects. Pharmacol Biochem Behav 66:563–572

    Article  PubMed  CAS  Google Scholar 

  • King A, Cao D, Vanier C, Wilcox T (2009) Naltrexone decreases heavy drinking rates in smoking cessation treatment: an exploratory study. Alcohol Clin Exp Res 33:1044–1050

    Article  PubMed  CAS  Google Scholar 

  • King A, McNamara P, Angstadt M, Phan KL (2010) Neural substrates of alcohol-induced smoking urge in heavy drinking nondaily smokers. Neuropsychopharmacology 35:692–701

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Krishnan-Sarin S, Wand GS, Li XW, Portoghese PS, Froehlich JC (1998) Effect of mu opioid receptor blockade on alcohol intake in rats bred for high alcohol drinking. Pharmacol Biochem Behav 59:627

    Article  PubMed  CAS  Google Scholar 

  • Le AD, Poulos CX, Quan B, Chow S (1993) The effects of selective blockade of delta and mu opiate receptors on alcohol consumption by C57BL/6 mice in a restricted access paradigm. Brain Res 630:330–333

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Le 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Le AD, Lo S, Harding S, Juzytsch W, Marinelli PW, Funk D (2010) Coadministration of intravenous nicotine and oral alcohol in rats. Psychopharmacology (Berl) 208:475–486

    Article  CAS  Google Scholar 

  • Liu X, Palmatier MI, Caggiula AR, Sved AF, Donny EC, Gharib M, Booth S (2009) Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats. Psychopharmacology (Berl) 202:589–598

    Article  CAS  Google Scholar 

  • Marco EM, Granstrem O, Moreno E, Llorente R, Adriani W, Laviola G, Viveros MP (2007) Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats. Eur J Pharmacol 557:37–43

    Article  PubMed  CAS  Google Scholar 

  • Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Le AD (2007) The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl) 195:345–355

    Article  CAS  Google Scholar 

  • Marszalec W, Aistrup GL, Narahashi T (1999) Ethanol-nicotine interactions at alpha-bungarotoxin-insensitive nicotinic acetylcholine receptors in rat cortical neurons. Alcohol Clin Exp Res 23:439–445

    Article  PubMed  CAS  Google Scholar 

  • McCarthy MJ, Zhang H, Neff NH, Hadjiconstantinou M (2010) Desensitization of delta-opioid receptors in nucleus accumbens during nicotine withdrawal. Psychopharmacology (Berl)

  • McKee SA, O'Malley SS, Shi J, Mase T, Krishnan-Sarin S (2008) Effect of transdermal nicotine replacement on alcohol responses and alcohol self-administration. Psychopharmacology (Berl) 196:189–200

    Article  CAS  Google Scholar 

  • Mhatre M, Holloway F (2003) Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption. Alcohol 29:109–116

    Article  PubMed  CAS  Google Scholar 

  • National Academy of Sciences (2011) Guide for the care and use of laboratory animals, 8th edition. The National Academic Press, Washington, D.C.

  • Nielsen CK, Simms JA, Pierson HB, Li R, Saini SK, Ananthan S, Bartlett SE (2008) A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats. Biol Psychiatry 64:974–981

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Nil R, Buzzi R, Battig K (1984) Effects of single doses of alcohol and caffeine on cigarette smoke puffing behavior. Pharmacol Biochem Behav 20:583–590

    Article  PubMed  CAS  Google Scholar 

  • Olausson P, Ericson M, Lof E, Engel JA, Soderpalm B (2001) Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment. Eur J Pharmacol 417:117–123

    Article  PubMed  CAS  Google Scholar 

  • Palmatier MI, Wilkinson JL, Metschke DM, Bevins RA (2005) Stimulus properties of nicotine, amphetamine, and chlordiazepoxide as positive features in a pavlovian appetitive discrimination task in rats. Neuropsychopharmacology 30:731–741

    PubMed  CAS  Google Scholar 

  • Parnell SE, West JR, Chen WJ (2006) Nicotine decreases blood alcohol concentrations in adult rats: a phenomenon potentially related to gastric function. Alcohol Clin Exp Res 30:1408–1413

    Article  PubMed  CAS  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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rose JE, Brauer LH, Behm FM, Cramblett M, Calkins K, Lawhon D (2002) Potentiation of nicotine reward by alcohol. Alcohol Clin Exp Res 26:1930–1931

    Article  PubMed  CAS  Google Scholar 

  • Rose JE, Brauer LH, Behm FM, Cramblett M, Calkins K, Lawhon D (2004) Psychopharmacological interactions between nicotine and ethanol. Nicotine Tob Res 6:133–144

    Article  PubMed  CAS  Google Scholar 

  • Russell MA, Jarvis MJ, West RJ (1986) Use of urinary nicotine concentrations to estimate exposure and mortality from passive smoking in non-smokers. Br J Addict 81:275–281

    Article  PubMed  CAS  Google Scholar 

  • Sayette M (2002) The effects of alcohol on cigarette craving. Alcohol Clin Exp Res 26:1925–1927

    Article  PubMed  CAS  Google Scholar 

  • Sharpe AL, Samson HH (2002) Repeated nicotine injections decrease operant ethanol self-administration. Alcohol 28:1–7

    Article  PubMed  CAS  Google Scholar 

  • Stairs DJ, Neugebauer NM, Bardo MT (2010) Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats. Behav Pharmacol 21:182–193

    Article  PubMed  CAS  PubMed Central  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  PubMed  CAS  PubMed Central  Google Scholar 

  • Thiele TE, Navarro M (2013) “Drinking in the dark” (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Udo T, Harrison EL, Shi J, Tetrault J, McKee SA (2013) A preliminary study on the effect of combined nicotine replacement therapy on alcohol responses and alcohol self-administration. Am J Addict 22:590–597

    Article  PubMed  PubMed Central  Google Scholar 

  • Walker EA, Zernig G, Young AM (1998) In vivo apparent affinity and efficacy estimates for mu opiates in a rat tail-withdrawal assay. Psychopharmacology (Berl) 136:15–23

    Article  CAS  Google Scholar 

  • Walters CL, Cleck JN, Kuo YC, Blendy JA (2005) Mu-opioid receptor and CREB activation are required for nicotine reward. Neuron 46:933–943

    Article  PubMed  CAS  Google Scholar 

  • Wang AJ (2003) Nicotine and ethanol interactions. Master's thesis, University of Toronto

  • Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, McCaul ME (2008) Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology 33:653–665

    Article  PubMed  CAS  Google Scholar 

  • Wewers ME, Dhatt RK, Snively TA, Tejwani GA (1999) The effect of chronic administration of nicotine on antinociception, opioid receptor binding and met-enkephalin levels in rats. Brain Res 822:107–113

    Article  PubMed  CAS  Google Scholar 

  • Williams KL, Broadbridge CL (2009) Potency of naltrexone to reduce ethanol self-administration in rats is greater for subcutaneous versus intraperitoneal injection. Alcohol 43:119–126

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wise RA (2002) Brain reward circuitry: insights from unsensed incentives. Neuron 36:229–240

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from the NIAAA (AA13108) to A.D. Lê.

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Correspondence to Douglas Funk.

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Lê, A.D., Funk, D., Lo, S. et al. Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse. Psychopharmacology 231, 4019–4029 (2014). https://doi.org/10.1007/s00213-014-3541-2

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  • DOI: https://doi.org/10.1007/s00213-014-3541-2

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