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Nicotine preference and affective behavior of Cd81 knockout mice

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Abstract

Rationale

Cd81 -/- (knockout) mice have previously been reported to have reduced cocaine preference and increased striatal dopamine content and dopamine turnover, but normal learning and memory in the Morris water maze. The effects of Cd81 on other behaviors and drugs of abuse have not been investigated.

Objectives and methods

We measured the effects of Cd81 -/- in a modified two-bottle choice test for nicotine, as well as in somatic signs of nicotine withdrawal, four tests of affective behavior, and tyrosine hydroxylase gene expression assays.

Results

We found that Cd81 loss-of-function significantly increased voluntary nicotine consumption and somatic signs of nicotine withdrawal. Nicotine consumption of Cd81 -/- female mice increased for 3 weeks and then remained relatively stable for the next 5 weeks, suggesting that their nicotine consumption continued to be limited by aversion to higher nicotine doses. Cd81 -/- also produced a dramatic and significant increase in struggling in the forced swim test and a significant increase in the time spent in the light chamber of the light/dark box. The elevated plus maze and the tail suspension test did not show a main effect of genotype. Therefore, we conclude that Cd81 did not have an overall effect on anxiety- or depression-like behavior. Tyrosine hydroxylase mRNA levels were unchanged.

Conclusions

Cd81 knockouts have a strongly increased nicotine preference, plus a proactive response to specific stressful situations. Together with reports of increased striatal dopamine content and anecdotal reports of increased aggressiveness, these provide intriguing parallels to some aspects of post-traumatic stress disorder.

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References

  • Adriani W, Laviola G (2004) Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model. Behav Pharmacol 15:341–352

    Article  CAS  PubMed  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, fifth edition. American Psychiatric Association, Arlington, VA.

  • Astrup A, Hansen DL, Lundsgaard C, Toubro S (1998) Sibutramine and energy balance. Int J Obes Relat Metab Disord 22:S30–S42

    CAS  PubMed  Google Scholar 

  • Bahi A, Boyer F, Kafri T, Dreyer JL (2004) CD81-induced behavioural changes during chronic cocaine administration: in vivo gene delivery with regulatable lentivirus. Eur J Neurosci 19:1621–1633

    Article  PubMed  Google Scholar 

  • Bahi A, Boyer F, Kolira M, Dreyer JL (2005) In vivo gene silencing of CD81 by lentiviral expression of small interference RNAs suppresses cocaine-induced behaviour. J Neurochem 92:1243–1255

    Article  CAS  PubMed  Google Scholar 

  • Bali A, Jaggi AS (2015) Electric foot shock stress: a useful tool in neuropsychiatric studies. Rev Neurosci 26:655–677

    Article  PubMed  Google Scholar 

  • Ball TM, Stein MB (2012) Classification of posttraumatic stress disorder. In: Beck JG, Sloan DM (eds) The Oxford Handbook of Traumatic Stress Disorders. Oxford University Press, New York, pp 39-53

  • Basso AM, Gallagher KB, Bratcher NA, Brioni JD, Moreland RB, Hsieh GC, Drescher K, Fox GB, Decker MW, Rueter LE (2005) Antidepressant-Like effect of D2/3 receptor-, but not D4 receptor-activation in the rat forced swim test. Neuropsychopharmacology 30:1257–1268

    Article  CAS  PubMed  Google Scholar 

  • Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bisset GW, Fairhall KM (1995) The effect of cholinoceptor agonists and neurotoxins on the release of vasopressin in the rat in relation to the subunit composition of the cholinoceptor. Neurosci Lett 188:77–80

    Article  CAS  PubMed  Google Scholar 

  • Bourin M, Hascoët M (2003) The mouse light/dark box test. Eur J Pharmacol 463:55–65

    Article  CAS  PubMed  Google Scholar 

  • Bradski G, Kaehler A (2008) Learning OpenCV: Computer vision with the OpenCV library. O'Reilly Media, Sebastopol, CA.

  • BrenzVerca MS, Widmer DA, Wagner GC, Dreyer J (2001) Cocaine-induced expression of the tetraspanin CD81 and its relation to hypothalamic function. Mol Cell Neurosci 17:303–316

    Article  CAS  Google Scholar 

  • Breslau N, Davis GC, Schultz LR (2003) Posttraumatic stress disorder and the incidence of nicotine, alcohol, and other drug disorders in persons who have experienced trauma. Arch Gen Psychiatry 60:289–294

    Article  PubMed  Google Scholar 

  • Breslau N, Kilbey M, Andreski P (1991) Nicotine dependence, major depression, and anxiety in young adults. Arch Gen Psychiatry 48:1069–1074

    Article  CAS  PubMed  Google Scholar 

  • Breslau N, Peterson EL, Schultz LR, Chilcoat HD, Andreski P (1998) Major depression and stages of smoking: a longitudinal investigation. Arch Gen Psychiatry 55:161–166

    Article  CAS  PubMed  Google Scholar 

  • Brielmaier J, McDonald CG, Smith RF (2012) Effects of acute stress on acquisition of nicotine conditioned place preference in adolescent rats: a role for corticotropin-releasing factor 1 receptors. Psychopharmacology 219:73–82

    Article  CAS  PubMed  Google Scholar 

  • Brielmaier JM, McDonald CG, Smith RF (2008) Nicotine place preference in a biased conditioned place preference design. Pharmacol Biochem Behav 89:94–100

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Evans G (1990) A simple screening method for transgenic mice using the polymerase chain reaction. Biotechniques 8:32–33

    CAS  PubMed  Google Scholar 

  • Commons KG, Cholanians AB, Babb JA, Ehlinger DG (2017) The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci 8:955–960

    Article  CAS  PubMed  Google Scholar 

  • Crowley JJ, Blendy JA, Lucki I (2005) Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test. Psychopharmacology 183:257–264

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Kelly PH, Neijt HC, Sansig G, Flor PJ, van Der Putten H (2003) Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. Eur J Neurosci 17:2409–2417

    Article  PubMed  Google Scholar 

  • Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625

    Article  CAS  PubMed  Google Scholar 

  • Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berlin) 121:66–72

  • Dharker N (2012) Gene expression responses to single and repeated nicotine injections in adolescent and adult mice. PhD Dissertation, School of Systems Biology, George Mason University, Fairfax, VA.

  • Dudas MM, George TP (2005) Non-nicotine pharmacotherapies for nicotine dependence. Essent Psychopharmacol 6:158–172

    PubMed  Google Scholar 

  • Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91:1025–1043

    Article  CAS  PubMed  Google Scholar 

  • Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79

    Article  CAS  PubMed  Google Scholar 

  • Field A (2005) Discovering statistics using SPSS. SAGE Publications, Los Angeles, CA

  • Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ (2011) Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471:597–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frederick SL, Reus VI, Ginsberg D, Hall SM, Munoz RF, Ellman G (1998) Cortisol and response to dexamethasone as predictors of withdrawal distress and abstinence success in smokers. Biol Psychiatry 43:525–530

    Article  CAS  PubMed  Google Scholar 

  • Geisert EE Jr, Williams RW, Geisert GR, Fan L, Asbury AM, Maecker HT, Deng J, Levy S (2002) Increased brain size and glial cell number in CD81-null mice. J Comp Neurol 453:22–32

    Article  PubMed  Google Scholar 

  • Gervasi NM, Scott SS, Aschrafi A, Gale J, Vohra SN, MacGibeny MA, Kar AN, Gioio AE, Kaplan BB (2016) The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons. RNA 22:883–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA (2004) Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 61:1107–1115

    Article  PubMed  Google Scholar 

  • Grieder TE, Herman MA, Contet C, Tan LA, Vargas-Perez H, Cohen A, Chwalek M, Maal-Bared G, Freiling J, Schlosburg JE, Clarke L, Crawford E, Koebel P, Repunte-Canonigo V, Sanna PP, Tapper AR, Roberto M, Kieffer BL, Sawchenko PE, Koob GF, van der Kooy D, George O (2014) VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci 17:1751–1758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hallgren KA (2012) Computing inter-rater reliability for observational data: an overview and tutorial. Tutor Quant Methods Psychol 8:23–34

    Article  PubMed  PubMed Central  Google Scholar 

  • Heim C, Nemeroff CB (2016) Neurobiological pathways involved in fear, stress, and PTSD. In: Liberzon I, Ressler KJ (eds) Neurobiology of PTSD: from Brain to Mind. Oxford Univ. Press, New York, pp 220-238

  • Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811

    Article  CAS  PubMed  Google Scholar 

  • Hudson AD, Murphy RL, Peglar MT, Fryxell KJ (2019) Alternative splicing of D2 dopamine receptor mRNA shows little difference between neuronal cell types, but is modulated by nicotine and the sex of the individual. Soc Neurosci Meeting Planner Online Program 773: 16

  • Jorm AF (1999) Association between smoking and mental disorders: results from an Australian National Prevalence Survey. Aust N Z J Public Health 23:245–248

    Article  CAS  PubMed  Google Scholar 

  • Keppel G, Wickens TD (2004) Design and analysis: a researcher's handbook, 4th edn. Pearson Prentice Hall, Upper Saddle River, New Jersey

  • Khantzian EJ (1997) The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harvard Rev Psychiatry 4:231–244

    Article  CAS  Google Scholar 

  • Koob GF (2011) Animal models of drug dependence: motivational perspective. In: Johnson BA (ed) Addiction Medicine. Springer, New York, pp 333-357

  • Koob GF, Le Moal M (2006) Nicotine. In: Koob GF, Le Moal M (eds) Neurobiology of Addiction. Academic Press, New York, pp 243-287

  • Kumer SC, Vrana KE (1996) Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 67:443–462

    Article  CAS  PubMed  Google Scholar 

  • Lenartowski R, Goc A (2011) Epigenetic, transcriptional and posttranscriptional regulation of the tyrosine hydroxylase gene. Int J Dev Neurosci 29:873–883

    Article  CAS  PubMed  Google Scholar 

  • Levy S, Shoham T (2005) The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5:136–148

    Article  CAS  PubMed  Google Scholar 

  • Locklear LL, McDonald CG, Smith RF, Fryxell KJ (2012) Adult mice voluntarily progress to nicotine dependence in an oral self-selection assay. Neuropharmacology 63:582–592

    Article  CAS  PubMed  Google Scholar 

  • Ludvig J, Miner B, Eisenberg MJ (2005) Smoking cessation in patients with coronary artery disease. Am Heart J 149:565–572

    Article  PubMed  Google Scholar 

  • Maecker HT, Levy S (1997) Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J Exp Med 185:1505–1510

    Article  CAS  PubMed  PubMed Central  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 43:779–784

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447:1111–1115

    Article  CAS  PubMed  Google Scholar 

  • McKenzie M, Olsson CA, Jorm AF, Romaniuk H, Patton GC (2010) Association of adolescent symptoms of depression and anxiety with daily smoking and nicotine dependence in young adulthood: findings from a 10-year longitudinal study. Addiction 105:1652–1659

    Article  PubMed  Google Scholar 

  • Melia KR, Trembleau A, Oddi R, Sanna PP, Bloom FE (1994) Detection and regulation of tyrosine hydroxylase mRNA in catecholaminergic terminal fields: possible axonal compartmentalization. Exp Neurol 130:394–406

    Article  CAS  PubMed  Google Scholar 

  • Meyers LS, Gamst G, Guarino AJ (2006) Applied multivariate research: design and interpretation. Sage Publications, Thousand Oaks, CA

  • Michna L, BrenzVerca MS, Widmer DA, Chen S, Lee J, Rogove J, Zhou R, Tsitsikov E, Miescher GC, Dreyer JL, Wagner GC (2001) Altered sensitivity of CD81-deficient mice to neurobehavioral effects of cocaine. Mol Brain Res 90:68–74

    Article  CAS  PubMed  Google Scholar 

  • Murphy KR, Myors B (2004) Statistical power analysis: a simple and general model for traditional and modern hypothesis tests, 2nd edn. Lawrence Erlbaum Associates, Mahwah, New Jersey

  • Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC (1993) Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 90:8424–8428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nestler EJ, Carlezon WAJ (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151–1159

    Article  CAS  PubMed  Google Scholar 

  • O’Dell LE (2009) A psychobiological framework of the substrates that mediate nicotine use during adolescence. Neuropharmacology 56:263–278

  • Olson CL (1976) On choosing a test statistic in MANOVA. Psychol Bull 83:579–586

    Article  Google Scholar 

  • Pan Y, Geisert D, Orr W, Geisert E (2011) The effects of a Cd81 null mutation on retinal pigment epithelium in mice. Neurochem Res 36:569–573

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC (1999) Does cigarette smoking cause stress? Am Psychol 54:817–820

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC (2000) Cigarette smoking does cause stress. Am Psychol 55:1159–1160

    Article  CAS  PubMed  Google Scholar 

  • Perkins KA, Epstein LH, Stiller RL, Marks BL, Jacob RG (1989) Acute effects of nicotine on resting metabolic rate in cigarette smokers. Am J Clin Nutr 50:545–550

    Article  CAS  PubMed  Google Scholar 

  • Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 177:245–255

    Article  CAS  PubMed  Google Scholar 

  • Polesskaya OO, Fryxell KJ, Merchant AD, Locklear LL, Ker KF, McDonald CG, Eppolito AK, Smith LN, Wheeler TL, Smith RF (2007a) Nicotine causes age-dependent changes in gene expression in the adolescent female rat brain. Neurotoxicol Teratol 29:126–140

    Article  CAS  PubMed  Google Scholar 

  • Polesskaya OO, Smith RF, Fryxell KJ (2007b) Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats. Biol Psychiatry 61:56–64

    Article  CAS  PubMed  Google Scholar 

  • Pomerleau OF, Pomerleau CS, Mehringer AM, Snedecor SM, Ninowski R, Sen A (2005) Nicotine dependence, depression, and gender: characterizing phenotypes based on withdrawal discomfort, response to smoking, and ability to abstain. Nicotine Tob Res 7:91–102

    Article  PubMed  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn 229:327–336

    CAS  PubMed  Google Scholar 

  • Ren S, Li M, Cai H, Hudgins S, Furth PA (2001) A simplified method to prepare PCR template DNA for screening of transgenic and knockout mice. J Am Assoc Lab Anim Sci 40:27–30

    CAS  Google Scholar 

  • Russo SJ, Murrough JW, Han M-H, Charney DS, Nestler EJ (2012) Neurobiology of resilience. Nat Neurosci 15:1475–1484

  • Sanyal M, Fernandez R, Levy S (2009) Enhanced B cell activation in the absence of CD81. Int Immunol 21:1225–1237

    Article  CAS  PubMed  Google Scholar 

  • Sonntag H, Wittchen HU, Hofler M, Kessler RC, Stein MB (2000) Are social fears and DSM-IV social anxiety disorder associated with smoking and nicotine dependence in adolescents and young adults? Eur Psychiatry 15:67–74

    Article  CAS  PubMed  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  CAS  PubMed  Google Scholar 

  • Stevens JP (2009) Applied Multivariate Statistics for the Social Sciences, 5th edn. Routledge, New York

  • Tipps ME, Raybuck JD, Lattal KM (2014) Substance abuse, memory, and post-traumatic stress disorder. Neurobiol Learn Mem 112:87–100

    Article  PubMed  Google Scholar 

  • Toropova KA, Anokhin KV (2019) Modeling of post-traumatic stress disorder in mice: nonlinear relationship with the strength of the traumatic event. Neurosci Behav Physiol 49:875–886

    Article  Google Scholar 

  • Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537–541

    Article  CAS  PubMed  Google Scholar 

  • Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodward LJ, Fergusson DM (2001) Life course outcomes of young people with anxiety disorders in adolescence. J Am Acad Child Adolesc Psychiatry 40:1086–1093

    Article  CAS  PubMed  Google Scholar 

  • Xenias HS, Ibanez-Sandoval O, Koos T, Tepper JM (2015) Are striatal tyrosine hydroxylase interneurons dopaminergic? J Neurosci 35:6584–6599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Dr. Shoshana Levy for helpful comments, and particularly for the gift of Cd81 -/- (knockout) mice. We also thank Robert Hallenberg for helpful comments, Stephen Traskos and Jaidep Singh for assistance with the nicotine withdrawal experiments, and Katharina Scholz for assistance with the light/dark box assay. The computational image analysis software used in this project was written by ADH, based on algorithms suggested by KJF and software packages selected by RLM.

Funding

Research in this report was supported by the Virginia Youth Tobacco Programs (VYTP) and the Virginia Foundation for Healthy Youth (VFHY).

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Author notes

  1. R. Logan Murphy and Laura L. Locklear are the first two authors and contributed equally to this work.

Authors and Affiliations

  1. School of Systems Biology, and the Interdisciplinary Program in Neurosciences, George Mason University, Mail Stop 1J1, Institute of Advanced Biomedical Research Building, 10920 George Mason Circle, Manassas, VA, 20110, USA

    R. Logan Murphy, Laura L. Locklear, M. Haris Niaz, Rebecca L. Walton, Alexandra D. Hudson & Karl J. Fryxell

  2. Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA

    R. Logan Murphy

  3. Thomas Jefferson High School for Science and Technology, Alexandria, VA, USA

    Laura L. Locklear

  4. Lawrence Livermore National Laboratory, Livermore, CA, USA

    Rebecca L. Walton

  5. Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA, USA

    Alexandra D. Hudson

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  1. R. Logan Murphy
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Correspondence to Karl J. Fryxell.

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All animal procedures were approved by the George Mason University Institutional Animal Care and Use Committee, and were in accordance with the guidelines published in the “Guide for the Care and Use of Laboratory Animals” adopted by the National Institutes of Health.

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Murphy, R.L., Locklear, L.L., Niaz, M.H. et al. Nicotine preference and affective behavior of Cd81 knockout mice. Psychopharmacology 238, 3477–3497 (2021). https://doi.org/10.1007/s00213-021-05966-w

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