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.
Similar content being viewed by others
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
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
Bienkowski P, Kostowski W, Koros E (1999) Ethanol-reinforced behaviour in the rat: effects of naltrexone. Eur J Pharmacol 374:321–327
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
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
Chen WJ, Parnell SE, West JR (2001) Nicotine decreases blood alcohol concentration in neonatal rats. Alcohol Clin Exp Res 25:1072–1077
Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473–478
Corrigall WA, Coen KM (1991) Opiate antagonists reduce cocaine but not nicotine self-administration. Psychopharmacology (Berl) 104:167–170
Corrigall WA, Herling S, Coen KM (1988) Evidence for opioid mechanisms in the behavioral effects of nicotine. Psychopharmacology (Berl) 96:29–35
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
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
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
Dani JA, Harris RA (2005) Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci 8:1465–1470
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
Dohrman DP, Reiter CK (2003) Ethanol modulates nicotine-induced upregulation of nAChRs. Brain Res 975:90–98
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
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
Feyerabend C, Ings RM, Russel MA (1985) Nicotine pharmacokinetics and its application to intake from smoking. Br J Clin Pharmacol 19:239–247
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
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
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
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
Glautier S, Clements K, White JA, Taylor C, Stolerman IP (1996) Alcohol and the reward value of cigarette smoking. Behav Pharmacol 7:144–154
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
Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 111:855–876
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
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
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
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
King AC, Meyer PJ (2000) Naltrexone alteration of acute smoking response in nicotine-dependent subjects. Pharmacol Biochem Behav 66:563–572
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
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
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
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
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
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
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
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
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
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
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
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
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
Mhatre M, Holloway F (2003) Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption. Alcohol 29:109–116
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
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
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
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
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
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
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
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
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
Sayette M (2002) The effects of alcohol on cigarette craving. Alcohol Clin Exp Res 26:1925–1927
Sharpe AL, Samson HH (2002) Repeated nicotine injections decrease operant ethanol self-administration. Alcohol 28:1–7
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
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
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
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
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
Walters CL, Cleck JN, Kuo YC, Blendy JA (2005) Mu-opioid receptor and CREB activation are required for nicotine reward. Neuron 46:933–943
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
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
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
Wise RA (2002) Brain reward circuitry: insights from unsensed incentives. Neuron 36:229–240
Acknowledgments
This work was supported by a grant from the NIAAA (AA13108) to A.D. Lê.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-014-3541-2