, Volume 196, Issue 3, pp 483–495 | Cite as

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

  • Danielle Gulick
  • Thomas J. Gould
Original Investigation


Objective and rationale

Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice.

Materials and methods

Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training.


Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg−1 day−1) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning.


The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.


Addiction Learning Withdrawal Tolerance Acetylcholine 



This work was supported by National Institute on Alcohol Abuse and Alcoholism (NIAAA) Grant AA015515 (T.J.G.). All research complies with current US laws for the care and use of laboratory animals.


  1. Alkondon M, Albuquerque EX (2001) Nicotinic acetylcholine receptor a7 and a4b2 subtypes differentially control GABAergic input to CA1 neurons in rat hippocampus. J Neurophys 86:3043–3055Google Scholar
  2. Bammer G, Chesher GB (1982) An analysis of some effects of ethanol on performance in a passive avoidance task. Psychopharmacology 77:66–73PubMedCrossRefGoogle Scholar
  3. Bowers BJ, McClure-Begley TD, Keller JJ, Paylor R, Collins AC, Wehner JM (2005) Deletion of the α7 nicotinic receptor subunit gene results in increased sensitivity to several behavioral effects produced by alcohol. Alcohol Clin Exp Res 29(3):295–302PubMedCrossRefGoogle Scholar
  4. Celerier A, Ognard R, Decorte L, Beracochea D (2000) Deficits of spatial and non-spatial memory and of auditory fear conditioning following anterior thalamic lesions in mice: comparison with chronic alcohol consumption. Eur J Neurosci 12:2575–2584PubMedCrossRefGoogle Scholar
  5. Chen WJ, Parnell SE, West JR (2001) Nicotine decreases blood alcohol concentration in neonatal rats. Alcohol Clin Exp Res 23(1):18–25Google Scholar
  6. Collins AC, Burch JB, DeFiebre CM, Marks MJ (1988) Tolerance to and cross-tolerance between ethanol and nicotine. Pharmacol Biochem Behav 29:365–373PubMedCrossRefGoogle Scholar
  7. Collins AC, Romm E, Selvaag S, Turne S, Marks MJ (1993) A comparison of the effects of chronic nicotine infusion on tolerance to nicotine and cross-tolerance to ethanol in long- and short-sleep mice. J Pharmacol Exp Ther 266(3):1390–1397PubMedGoogle Scholar
  8. Collins AC, Wilkins LH, Slobe BS, Cao JZ, Bullock AE (1996) Long-term ethanol and nicotine treatment elicit tolerance to ethanol. Alcohol Clin Exp Res 20(6):990–999PubMedCrossRefGoogle Scholar
  9. Davis JA, James JR, Siegel SJ, Gould TJ (2005a) Withdrawal from chronic nicotine administration impairs contextual fear conditioning in C57BL/6 mice. J Neurosci 25:8708–8713PubMedCrossRefGoogle Scholar
  10. Davis JA, Porter J, Gould TJ (2005b) Nicotine enhances both foreground and background contextual fear conditioning. Neurosci Lett 394(3):202–205PubMedCrossRefGoogle Scholar
  11. Davis JA, Kenney JW, Gould TJ (2007) Hippocampal alpha4beta2 nicotinic acetylcholine receptor involvement in the enhancing effect of acute nicotine on contextual fear conditioning. J Neurosci 27:10870–10877PubMedCrossRefGoogle Scholar
  12. Dawson DA (2000) Drinking as a risk factor for sustained smoking. Drug Alcohol Depend 59:235–249PubMedCrossRefGoogle Scholar
  13. Escher T, Mittleman G (2004) Effects of ethanol and GABAb drugs on working memory. Psychopharmacology 176:166–174PubMedCrossRefGoogle Scholar
  14. Forman SA, Zhou Q (1999) Novel modulation of a nicotinic receptor channel mutant reveals that the open state is stabilized by ethanol. Mol Pharmacol 55:102–108PubMedGoogle Scholar
  15. Friend KB, Pagano ME (2005) Changes in cigarette consumption and drinking outcomes: findings from Project MATCH. J Subst Abuse Treat 29(3):221–229PubMedCrossRefGoogle Scholar
  16. Gibson WE (1985) Effects of alcohol on radial maze performance in rats. Physiol Behav 35:1003–1005PubMedCrossRefGoogle Scholar
  17. Gould TJ (2003a) Ethanol disrupts fear conditioning in C57BL/6J mice. J Psychopharmacol 17(1):77–81PubMedCrossRefGoogle Scholar
  18. Gould TJ (2003b) Nicotine produces a within-subject enhancement of contextual fear conditioning in C57BL/6 mice independent of sex. Integr Physiol Behav Sci 38(2):124–132PubMedCrossRefGoogle Scholar
  19. Gould TJ, Higgins JS (2003) Nicotine enhances contextual fear conditioning in C57BL/6J mice at 1 and 7 days post-training. Neurobiol Learn Mem 80:147–157PubMedCrossRefGoogle Scholar
  20. Gould TJ, Lommock JA (2003) Nicotine enhances contextual fear conditioning and ameliorates ethanol-induced deficits in contextual fear conditioning. Behav Neurosci 117(6):1276–1282PubMedCrossRefGoogle Scholar
  21. Gould TJ, Wehner JM (1999) Nicotine enhancement of contextual fear conditioning. Behav Brain Res 102(1–2):31–39PubMedCrossRefGoogle Scholar
  22. Gould TJ, Feiro O, Moore D (2004) Nicotine enhances trace cued fear conditioning but not delay cued fear conditioning. Behav Brain Res 155(1):167–173PubMedCrossRefGoogle Scholar
  23. Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA (1996) Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716PubMedCrossRefGoogle Scholar
  24. Gulick D, Gould TJ (2007) Acute ethanol has biphasic effects on short- and long-term memory in both foreground and background contextual feat conditioning in C57BL/6 mice. Alcohol Clin Exp Res 31(9):1528–1537PubMedCrossRefGoogle Scholar
  25. Hahn B, Shoaib M, Stolerman I (2002) Nicotine-induced enhancement of attention in the five-choice serial reaction time task: the influence of task demands. Psychopharmacology 162(2):129–137PubMedCrossRefGoogle Scholar
  26. Hernandez LL, Powell DA (1986) Ethanol enhancement of Pavlovian conditioning: comparison with instrumental conditioning. Psychopharmacology 88:75–81PubMedCrossRefGoogle Scholar
  27. Hernandez LL, Valentine JD (1990) Mild ethanol intoxication may enhance Pavlovian conditioning. Drug Dev Res 20:155–167CrossRefGoogle Scholar
  28. Higgins ST, Rush CR, Hughes JR, Bickel WK, Lynn M, Capeless MA (1992) Effects of cocaine and alcohol, alone and in combination, on human learning and performance. J Exp Anal Behav 58(1):87–105PubMedCrossRefGoogle Scholar
  29. Hyman EH, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598PubMedCrossRefGoogle Scholar
  30. John U, Meyer C, Rumpf HJ, Hake U (2003) Probabilities of alcohol high-risk drinking, abuse, or dependence estimated on grounds of tobacco smoking and nicotine dependence. Addiction 98:805–814PubMedCrossRefGoogle Scholar
  31. Kalivas PW, O’Brien C (2007) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology (in press)Google Scholar
  32. Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179PubMedCrossRefGoogle Scholar
  33. Kelley BM, Rowan JD (2004) Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice. Int J Dev Neurosci 22(5–6):339–348PubMedCrossRefGoogle Scholar
  34. Kunin D, Smith BR, Amit Z (1999) Nicotine and ethanol interaction on conditioned taste aversions induced by both drugs. Pharmacol Biochem Behav 62(2):215–221PubMedCrossRefGoogle Scholar
  35. Larsson A, Engel JA (2004) Neurochemical and behavioral studies on ethanol and nicotine interactions. Neurol Biobehav Rev 27:713–720CrossRefGoogle Scholar
  36. Larsson A, Svensson L, Soderpalm B, Engel JA (2002) Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice. Alcohol 28:157–167PubMedCrossRefGoogle Scholar
  37. Lewis MC, Gould TJ (2005) Latent inhibition of cued fear conditioning: an NMDA receptor-dependent process that can be established in the presence of anisomycin. Eur J Neurosci 20(3):818–826CrossRefGoogle Scholar
  38. Lima-Landman MT, Albuquerque EX (1989) Ethanol potentiates and blocks NMDA-activated single-channel currents in rat hippocampal pyramidal cells. FEBS Lett 247(1):61–67PubMedCrossRefGoogle Scholar
  39. Logue SF, Paylor R, Wehner JM (1997) Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. Behav Neurosci 111(1):104–133PubMedCrossRefGoogle Scholar
  40. Lopez MF, White N, Randall CL (2001) Alcohol tolerance and nicotine cross-tolerance in adolescent mice. Add Biol 6:119–127CrossRefGoogle Scholar
  41. Lyon RJ, Tong JE, Leigh G, Clare G (1975) The influence of alcohol and tobacco on the components of choice reaction time. J Stud Alcohol 36(5):587–596PubMedGoogle Scholar
  42. Madden PAF, Heath AC, Starner GA, Whitfield JB, Martin NG (1995) Alcohol sensitivity and smoking history in men and women. Alcohol Clin Exp Res 19(5):1111–1120PubMedCrossRefGoogle Scholar
  43. McKee SA, Kishnan-Sarin S, Shi J, Mase T, O’Malley SS (2006) Modeling the effect of alcohol on smoking lapse behavior. Psychopharmacology 189(2):201–210PubMedCrossRefGoogle Scholar
  44. Melia KR, Ryabinin AE, Corodimas KP, Wilson MC, LeDoux JE (1996) Hippocampal-dependent learning and experience-dependent activation of the hippocampus are preferentially disrupted by ethanol. Neuroscience 74(2):313–322PubMedCrossRefGoogle Scholar
  45. Meyerhoff DJ (Chair), Tizabi Y, Staley JK, Durazzo TC, Glass JM, Nixon SJ (2006) Smoking comorbidity in alcoholism: neurobiological and neurocognitive consequences. Symposium conducted for Alcohol Clin Exp Res 30(2):253–264CrossRefGoogle Scholar
  46. Palfai TP, Monti PM, Ostafin B, Hutchison K (2000) Effects of nicotine deprivation on alcohol-related information processing and drinking behavior. J Abnorm Psychology 109(1):96–105CrossRefGoogle Scholar
  47. 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(8):1408–1413PubMedCrossRefGoogle Scholar
  48. Patkar A, Mannelli P, Peindl K, Murray HW, Meier B, Leone FT (2006) Changes in tobacco smoking following treatment for cocaine dependence. Am J Drug Alcohol Abuse 32(2):135–148PubMedCrossRefGoogle Scholar
  49. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106(2):274–285PubMedCrossRefGoogle Scholar
  50. Rezvani AH, Levin ED (2003) Nicotine-alcohol interactions and attentional performance on an operant visual signal detection task in female rats. Pharmacol Biochem Behav 76:75–83PubMedCrossRefGoogle Scholar
  51. Sobel BF, Sigmon SC, Griffiths RR (2004) Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers. Neuropsychopharmacology 29(5):991–1003PubMedCrossRefGoogle Scholar
  52. Tizabi Y, Bai L, Copeland RL, Taylor RE (2007) Combined effects of systemic alcohol and nicotine on dopamine release in the nucleus accumbens shell. Alcohol Alcohol 42:413–416PubMedGoogle Scholar
  53. Vihavainen T, Mijatovic J, Piepponen TP, Tuominen RK, Ahtee L (2006) Effect of morphine on locomotor activity and striatal monoamine metabolism in nicotine-withdrawn mice. Behav Brain Res 173(1):85–93PubMedCrossRefGoogle Scholar
  54. Wehner JM, Keller JJ, Keller AB, Picciotto MR, Paylor R, Booker TK, Beaudet A, Heinemann SF, Balogh SA (2004) Role of nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning. Neuroscience 129:11–24PubMedCrossRefGoogle Scholar
  55. Weitemier AZ, Ryabinin AE (2003) Alcohol-induced memory impairment in trace fear conditioning: a hippocampus-specific effect. Hippocampus 13:305–315PubMedCrossRefGoogle Scholar
  56. White AM, Matthews DB, Best PJ (2000) Ethanol, memory, and hippocampal function: a review of recent findings. Hippocampus 10:88–93PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of Psychology, Neuroscience ProgramTemple UniversityPhiladelphiaUSA
  2. 2.Department of Psychology, Center for Substance Abuse ResearchTemple UniversityPhiladelphiaUSA

Personalised recommendations