Skip to main content
SpringerLink
Log in

Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

  • Original Research
  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  • André JM, Gulick D, Portugal GS, Gould TJ (2008) Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice. Behav Brain Res 190(2):174–181

    Article  PubMed  Google Scholar 

  • Auerbach AB, Norinsky R, Ho W, Losos K, Guo Q, Chatterjee S, Joyner AL (2003) Strain-dependent differences in the efficiency of transgenic mouse production. Transgenic Res 12(1):59–69

    Article  PubMed  Google Scholar 

  • Balogh SA, Wehner JM (2003) Inbred mouse strain differences in the establishment of long-term fear memory. Behav Brain Res 140(1–2):97–106

    Article  PubMed  Google Scholar 

  • Benowitz NL (1988) Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N Engl J Med 319(20):1318–1330

    Article  PubMed  Google Scholar 

  • Benowitz NL, Jacob P III (1994) Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56(5):483–493

    Article  PubMed  Google Scholar 

  • Blanchard RJ, Blanchard DC (1969) Crouching as an index of fear. J Comp Physiol Psych 67(3):370–375

    Article  Google Scholar 

  • Bolivar VJ, Pooler O, Flaherty L (2001) Inbred strain variation in contextual and cued fear conditioning behavior. Mamm Genome 12(8):651–656

    Article  PubMed  Google Scholar 

  • Bowers BJ, Christensen SC, Pauley JR, Paylor R, Yuva L, Dunbar SE, Wehner JM (1995) Protein and molecular characterization of hippocampal protein kinase C in C57BL/6 and DBA/2 mice. J Neurochem 64(6):2737–2746

    Article  PubMed  Google Scholar 

  • Boyle AE, Gill KJ (2009) Genetic analysis of the psychostimulant effects of nicotine in chromosome substitution strains and F2 crosses derived from A/J and C57BL/6J progenitors. Mamm Genome 20(1):34–42

    Article  PubMed  Google Scholar 

  • Cahill K, Stead LF, Lancaster T (2007) Nicotine receptor partial agonists for smoking cessation. Cochrane database of systematic reviews (Online) (1):CD006103

  • Collins AC, Miner LL, Marks MJ (1988) Genetic influences on acute responses to nicotine and nicotine tolerance in the mouse. Pharmacol Biochem Behav 30(1):269–278

    Article  PubMed  Google Scholar 

  • Committee on Standardized Genetic Nomenclature for Mice (1989) Rules for nomenclature of inbred strains. In: Lyon MF, Searle AG (eds) Genetic variants and strains of the laboratory mouse. Oxford University Press, New York, pp 632–635

  • Damaj MI, Kao W, Martin BR (2003) Characterization of spontaneous and precipitated nicotine withdrawal in the mouse. J Pharmacol Exp Ther 307(2):526–534

    Article  PubMed  Google Scholar 

  • Damaj MI, Fonck C, Marks MJ, Deshpande P, Labarca C, Lester HA, Collins AC, Martin BR (2007) Genetic approaches identify differential roles for alpha4beta2* nicotinic receptors in acute models of antinociception in mice. J Pharmacol Exp Ther 321(3):1161–1169

    Article  PubMed  Google Scholar 

  • Davis JA, Gould TJ (2006) The effects of DHBE and MLA on nicotine-induced enhancement of contextual fear conditioning in C57BL/6 mice. Psychopharmacology (Berl) 184(3–4):345–352

    Article  Google Scholar 

  • Davis JA, Gould TJ (2007a) Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning. Neuropsychopharmacology 32(9):2011–2019

    Article  PubMed  Google Scholar 

  • Davis JA, Gould TJ (2007b) beta2 subunit-containing nicotinic receptors mediate the enhancing effect of nicotine on trace cued fear conditioning in C57BL/6 mice. Psychopharmacology (Berl) 190(3):343–352

    Article  Google Scholar 

  • Davis JA, Gould TJ (2009) Hippocampal nAChRs mediate nicotine withdrawal-related learning deficits. Eur Neuropsychopharmacol 19(8):551–561

    Article  PubMed  Google Scholar 

  • Davis JA, James JR, Siegel SJ, Gould TJ (2005) Withdrawal from chronic nicotine administration impairs contextual fear conditioning in C57BL/6 mice. J Neurosci 25(38):8708–8713

    Article  PubMed  Google Scholar 

  • Davis JA, Porter J, Gould TJ (2006) Nicotine enhances both foreground and background contextual fear conditioning. Neurosci Lett 394(3):202–205

    Article  PubMed  Google Scholar 

  • 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(40):10870–10877

    Article  PubMed  Google Scholar 

  • Fordyce DE, Wehner JM (1992) Determination of hippocampal protein kinase C using a frozen tissue method: comparison of synaptosomal and total activity in C57BL/6 and DBA/2 mice. Biochem Biophys Res Commun 188(2):690–694

    Article  PubMed  Google Scholar 

  • Gill KJ, Boyle AE (2005) Genetic basis for the psychostimulant effects of nicotine: a quantitative trait locus analysis in AcB/BcA recombinant congenic mice. Genes Brain Behav 4(7):401–411

    Article  PubMed  Google Scholar 

  • Gould TJ, Higgins SJ (2003) Nicotine enhances contextual fear conditioning in C57BL/6J mice at 1 and 7 days post-training. Neurobiol Learn Mem 80(2):147–157

    Article  PubMed  Google Scholar 

  • Gould TJ, Wehner JM (1999) Nicotine enhancement of contextual fear conditioning. Behav Brain Res 102(1–2):31–39

    Article  PubMed  Google Scholar 

  • Gould TJ, Feiro O, Moore D (2004) Nicotine enhances trace cued fear conditioning but not delay cued fear conditioning in C57BL/6 mice. Behav Brain Res 155(1):167–173

    Article  PubMed  Google Scholar 

  • Grabus SD, Martin BR, Brown SE, Damaj MI (2006) Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists. Psychopharmacology (Berl) 184(3–4):456–463

    Article  Google Scholar 

  • Haberstick BC, Timberlake D, Ehringer MA, Lessem JM, Hopfer CJ, Smolen A, Hewitt JK (2007) Genes, time to first cigarette and nicotine dependence in a general population sample of young adults. Addiction (Abingdon, England) 102(4):655–665

    Google Scholar 

  • Hardie TL, Moss HB, Lynch KG (2006) Genetic correlations between smoking initiation and smoking behaviors in a twin sample. Addict Behav 31(11):2030–2037

    Article  PubMed  Google Scholar 

  • Ho MK, Tyndale RF (2007) Overview of the pharmacogenomics of cigarette smoking. Pharmacogenomics J 7(2):81–98

    Article  PubMed  Google Scholar 

  • Hughes JR, Stead LF, Lancaster T (2007) Antidepressants for smoking cessation. Cochrane database of systematic reviews (Online) (1):CD000031

  • Hukkanen J, Jacob P III, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57(1):79–115

    Article  PubMed  Google Scholar 

  • Jackson KJ, Martin BR, Changeux JP, Damaj MI (2008) Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther 325(1):302–312

    Article  PubMed  Google Scholar 

  • Jackson KJ, Walters CL, Miles MF, Martin BR, Damaj MI (2009) Characterization of pharmacological and behavioral differences to nicotine in C57Bl/6 and DBA/2 mice. Neuropharmacology 57(4):347–355

    Article  PubMed  Google Scholar 

  • Kubota T, Nakajima-Taniguchi C, Fukuda T, Funamoto M, Maeda M, Tange E, Ueki R, Kawashima K, Hara H, Fujio Y, Azuma J (2006) CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. Pharmacogenomics J 6(2):115–119

    Article  PubMed  Google Scholar 

  • Lee CW, Kahende J (2007) Factors associated with successful smoking cessation in the United States, 2000. Am J Public Health 97(8):1503–1509

    Article  PubMed  Google Scholar 

  • Li MD, Cheng R, Ma JZ, Swan GE (2003) A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction (Abingdon, England) 98(1):23–31

    Article  Google Scholar 

  • Li XC, Karadsheh MS, Jenkins PM, Brooks JC, Drapeau JA, Shah MS, Lautner MA, Stitzel JA (2007) Chromosomal loci that influence oral nicotine consumption in C57BL/6J × C3H/HeJ F2 intercross mice. Genes Brain Behav 6(5):401–410

    Article  PubMed  Google Scholar 

  • Logue SF, Owen EH, Rasmussen DL, Wehner JM (1997) Assessment of locomotor activity, acoustic and tactile startle, and prepulse inhibition of startle in inbred mouse strains and F1 hybrids: implications of genetic background for single gene and quantitative trait loci analyses. Neuroscience 80(4):1075–1086

    Article  PubMed  Google Scholar 

  • Malin DH, Lake JR, Newlin-Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43(3):779–784

    Article  PubMed  Google Scholar 

  • Marks MJ, Stitzel JA, Collins AC (1989a) Genetic influences on nicotine responses. Pharmacol Biochem Behav 33(3):667–678

    Article  PubMed  Google Scholar 

  • Marks MJ, Romm E, Campbell SM, Collins AC (1989b) Variation of nicotinic binding sites among inbred strains. Pharmacol Biochem Behav 33(3):679–689

    Article  PubMed  Google Scholar 

  • Marks MJ, Campbell SM, Romm E, Collins AC (1991) Genotype influences the development of tolerance to nicotine in the mouse. J Pharmacol Exp Ther 259(1):392–402

    PubMed  Google Scholar 

  • McIlvain H, Susman JL, Davis C, Gilbert C (1995) Physician counseling for smoking cessation: is the glass half empty? J Fam Pract 40(2):148–152

    PubMed  Google Scholar 

  • Naidong W, Shou W, Chen YL, Jiang X (2001) Novel liquid chromatographic-tandem mass spectrometric methods using silica columns and aqueous-organic mobile phases for quantitative analysis of polar ionic analytes in biological fluids. J Chromatogr 754(2):387–399

    Article  Google Scholar 

  • Owen EH, Logue SF, Rasmussen DL, Wehner JM (1997) Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: implications of genetic background for single gene mutations and quantitative trait loci analyses. Neuroscience 80(4):1087–1099

    Article  PubMed  Google Scholar 

  • Paylor R, Baskall L, Wehner JM (1993) Behavioral dissociations between C57BL/6 and DBA/2 mice on learning and memory tasks: A hippocampal-dysfunction hypothesis. Psychobiology 21(1):11–26

    Google Scholar 

  • Paylor R, Tracy R, Wehner J, Rudy JW (1994) DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning. Behav Neurosci 108(4):810–817

    Article  PubMed  Google Scholar 

  • Petersen DR, Norris KJ, Thompson JA (1984) A comparative study of the disposition of nicotine and its metabolites in three inbred strains of mice. Drug Metab Dispos 12(6):725–731

    PubMed  Google Scholar 

  • Pianezza ML, Sellers EM, Tyndale RF (1998) Nicotine metabolism defect reduces smoking. Nature 393(6687):750

    Article  PubMed  Google Scholar 

  • Plomin R, DeFries JC, McClearn GE (1990) Quantitative genetic theory. W. H. Freeman and Co., New York

    Google Scholar 

  • Portugal GS, Gould TJ (2007) Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning. Pharmacol Biochem Behav 88(2):179–187

    Article  PubMed  Google Scholar 

  • Portugal GS, Gould TJ (2008) Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research. Behav Brain Res 193(1):1–16

    Article  PubMed  Google Scholar 

  • Portugal GS, Kenney JW, Gould TJ (2008) beta2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning. Neurobiol Learn Mem 89(2):106–113

    Article  PubMed  Google Scholar 

  • Rao Y, Hoffmann E, Zia M, Bodin L, Zeman M, Sellers EM, Tyndale RF (2000) Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol Pharmacol 58(4):747–755

    PubMed  Google Scholar 

  • Raybuck JD, Gould TJ (2007) Extracellular signal-regulated kinase 1/2 involvement in the enhancement of contextual fear conditioning by nicotine. Behav Neurosci 121(5):1119–1124

    Article  PubMed  Google Scholar 

  • Raybuck JD, Portugal GS, Lerman C, Gould TJ (2008) Varenicline ameliorates nicotine withdrawal-induced learning deficits in C57BL/6 mice. Behav Neurosci 122(5):1166–1171

    Article  PubMed  Google Scholar 

  • Robinson SF, Marks MJ, Collins AC (1996) Inbred mouse strains vary in oral self-selection of nicotine. Psychopharmacology (Berl) 124(4):332–339

    Article  Google Scholar 

  • Salas R, Pieri F, De Biasi M (2004) Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24(45):10035–10039

    Article  PubMed  Google Scholar 

  • Salas R, Main A, Gangitano D, De Biasi M (2007) Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit. Neuropharmacology 53(7):863–869

    Article  PubMed  Google Scholar 

  • Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF (2004) Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 14(9):615–626

    Article  PubMed  Google Scholar 

  • Silagy C, Lancaster T, Stead L, Mant D, Fowler G (2004) Nicotine replacement therapy for smoking cessation. Cochrane database of systematic reviews (Online) (3):CD000146

  • Siu EC, Wildenauer DB, Tyndale RF (2006) Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5. Psychopharmacology (Berl) 184(3–4):401–408

    Article  Google Scholar 

  • Smith AM, Wehner JM (2002) Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice. Hippocampus 12(1):76–85

    Article  PubMed  Google Scholar 

  • Sullivan PF, Kendler KS (1999) The genetic epidemiology of smoking. Nicotine Tob Res 1(Suppl):2S51–2S57 discussion S69-70

    Google Scholar 

  • Wang D, Ma JZ, Li MD (2005) Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis. Pharmacogenomics J 5(3):166–172

    Article  PubMed  Google Scholar 

  • Wehner JM, Keller JJ, Keller AB, Picciotto MR, Paylor R, Booker TK, Beaudet A, Heinemann SF, Balogh SA (2004) Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning. Neuroscience 129(1):11–24

    Article  PubMed  Google Scholar 

  • Xian H, Scherrer JF, Madden PA, Lyons MJ, Tsuang M, True WR, Eisen SA (2003) The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine Tob Res 5(2):245–254

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge grant support from the National Institute on Drug Abuse (DA017949 TG; DA024787 TG), and the National Cancer Institute (CA143187 PI: Caryn Lerman PhD), and thank Dr. Randy James of Virginia Commonwealth University for his analysis of plasma samples.

Author information

Author notes

  1. George S. Portugal

    Present address: Department of Anesthesiology, Columbia University, New York, NY, 10032, USA

  2. Justin W. Kenney

    Present address: School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK

Authors and Affiliations

  1. Department of Psychology, Neuroscience Program, Temple University, Weiss Hall, Philadelphia, PA, 19122, USA

    George S. Portugal, Derek S. Wilkinson, Justin W. Kenney, Colleen Sullivan & Thomas J. Gould

Authors
  1. George S. Portugal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Derek S. Wilkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Justin W. Kenney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colleen Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas J. Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas J. Gould.

Additional information

Edited by Tamara Phillips.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Portugal, G.S., Wilkinson, D.S., Kenney, J.W. et al. Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning. Behav Genet 42, 133–150 (2012). https://doi.org/10.1007/s10519-011-9489-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-011-9489-7

Keywords

Search

Navigation