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Differentiating nicotine- versus schizophrenia-associated decreases of the α7 nicotinic acetylcholine receptor transcript, CHRFAM7A, in peripheral blood lymphocytes

  • Biological Psychiatry - Original Article
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Abstract

Nicotine addiction is prevalent in individuals with schizophrenia. Nicotine activation of nicotinic receptors (nAChRs) is time- and dose-dependent, but gene expression analyses often rely on qualitative self- or family-reported measures of smoking. We sought lymphocyte surrogates for cerebral α7-nAChR activity and tested if receptor transcription correlated with concurrently measured serum biomarkers for smoking [cotinine, C-reactive protein (CRP)]. PCR surveys to detect lymphocytic α7-related isoforms identified CHRFAM7A as the only consistently amplifiable transcript. In 20 smoking-matched people (n = 10 schizophrenia, n = 10 controls), we found significantly lower CHRFAM7A in cotinine and self-reported smokers versus nonsmokers (p ≤ 0.001–0.03) and an inverse correlation of cotinine with CHRFAM7A (p ≤ 0.04) in regression models. CHRFAM7A was not associated with diagnosis or CRP in any bi- or multi-variate analysis. Smoking-related CRP elevations only occurred in cotinine-based comparisons (p ≤ 0.03), and not when smoking was self-reported. Including biochemical indicators of serum nicotine can help differentiate smoking- versus disease-associated changes in nAChR expression.

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References

  • Becton-Dickinson BD (2003) Vacutainer CPT package insert. Becton, Dickinson and Company, New Jersey

    Google Scholar 

  • Breese CR, Lee MJ, Adams CE et al (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364

    Article  PubMed  CAS  Google Scholar 

  • Breslau N, Johnson EO (2000) Predicting smoking cessation and major depression in nicotine-dependent smokers. Am J Public Health 90:1122–1127

    Article  PubMed  CAS  Google Scholar 

  • Casey DE (2005) Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med 118:15S–22S

    PubMed  Google Scholar 

  • CDC (2005) Cigarette smoking among adults—United States, 2004. MMWR Morb Mortal Wkly Rep 54:1121–1124

    Google Scholar 

  • Chafetz L, White MC, Collins-Bride G et al (2005) The poor general health of the severely mentally ill: impact of schizophrenic diagnosis. Community Ment Health J 41:169–184

    Article  PubMed  Google Scholar 

  • Dalack GW, Healy DJ, Meador-Woodruff JH (1998) Nicotine dependence and schizophrenia: clinical phenomenon and laboratory findings. Am J Psychiatry 155:1490–1501

    PubMed  CAS  Google Scholar 

  • de Beaurepaire R, Lukasiewicz M, Beauverie P et al (2007) Comparison of self-reports and biological measures for alcohol, tobacco, and illicit drugs consumption in psychiatric inpatients. Eur Psychiatry 22:540–548

    Article  PubMed  Google Scholar 

  • De Luca V, Likhodi O, Van Tol HH et al (2006) Regulation of alpha7-nicotinic receptor subunit and alpha7-like gene expression in the prefrontal cortex of patients with bipolar disorder and schizophrenia. Acta Psychiatr Scand 114:211–215

    Article  PubMed  CAS  Google Scholar 

  • Dempster EL, Toulopoulou T, McDonald C et al (2006) Episodic memory performance predicted by the 2 bp deletion in exon 6 of the “alpha 7-like” nicotinic receptor subunit gene. Am J Psychiatry 163:1832–1834

    Article  PubMed  Google Scholar 

  • Dickerson F, Stallings C, Origoni A et al (2007) C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res 93:261–265

    Article  PubMed  Google Scholar 

  • Dietrich T, Garcia RI, de Pablo P et al (2007) The effects of cigarette smoking on C-reactive protein concentrations in men and women and its modification by exogenous oral hormones in women. Eur J Cardiovasc Prev Rehabil 14:694–700

    Article  PubMed  Google Scholar 

  • Fan X, Pristach C, Liu EY et al (2007) Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res 149:267–271

    Article  PubMed  CAS  Google Scholar 

  • Filik R, Sipos A, Kehoe PG et al (2006) The cardiovascular and respiratory health of people with schizophrenia. Acta Psychiatr Scand 113:298–305

    Article  PubMed  CAS  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (1996) Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV). American Psychiatric Press, Washington DC

    Google Scholar 

  • Fisher MA, Taylor GW, Shelton BJ et al (2007) Sociodemographic characteristics and diabetes predict invalid self-reported non-smoking in a population-based study of US adults. BMC Public Health 7:33

    Article  PubMed  Google Scholar 

  • Flomen RH, Collier DA, Osborne S et al (2006) Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 141B:571–575

    Article  PubMed  CAS  Google Scholar 

  • Freedman R, Hall M, Adler LE et al (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–33

    Article  PubMed  CAS  Google Scholar 

  • Freedman R, Coon H, Myles-Worsley M et al (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94:587–592

    Article  PubMed  CAS  Google Scholar 

  • Gault J, Robinson M, Berger R et al (1998) Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52:173–185

    Article  PubMed  CAS  Google Scholar 

  • Gault J, Hopkins J, Berger R et al (2003) Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. Am J Med Genet B Neuropsychiatr Genet 123B:39–49

    Article  PubMed  Google Scholar 

  • George TP, Vessicchio JC, Termine A (2003) Nicotine and tobacco use in schizophrenia. In: Meyer JM, Nasrallah HA (eds) Medical illness in schizophrenia. American Psychiatric Press, Washington DC

    Google Scholar 

  • Goff DC, Henderson DC, Amico E (1992) Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 149:1189–1194

    PubMed  CAS  Google Scholar 

  • Goff DC, Cather C, Evins AE et al (2005) Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry 66:183–194

    Article  PubMed  Google Scholar 

  • Guan ZZ, Zhang X, Blennow K et al (1999) Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. NeuroReport 10:1779–1782

    Article  PubMed  CAS  Google Scholar 

  • Heatherton TF, Kozlowski LT, Frecker RC et al (1991) The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 86:1119–1127

    Article  PubMed  CAS  Google Scholar 

  • Jones IW, Westmacott A, Chan E et al (2006) Alpha7 nicotinic acetylcholine receptor expression in Alzheimer’s disease: receptor densities in brain regions of the APP(SWE) mouse model and in human peripheral blood lymphocytes. J Mol Neurosci 30:83–84

    Article  PubMed  CAS  Google Scholar 

  • Kawashima K, Fujii T (2000) Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther 86:29–48

    Article  PubMed  CAS  Google Scholar 

  • Kimura R, Ushiyama N, Fujii T, Kawashima K (2003) Nicotine-induced Ca2+ signaling and down-regulation of nicotinic acetylcholine receptor subunit expression in the CEM human leukemic T cell line. Life Sci 72:2155–2158

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Postma P (2005) Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev 29:1021–1034

    Article  PubMed  CAS  Google Scholar 

  • Lai IC, Hong CJ, Tsai SJ (2001) Association study of a nicotinic receptor variant with schizophrenic disorders. Neuropsychobiology 43:15–18

    Article  PubMed  CAS  Google Scholar 

  • Leonard S, Adams C, Breese CR et al (1994) Schizophrenia and nicotinic receptors. Harv Rev Psychiatry 2:179–192

    Article  PubMed  Google Scholar 

  • Leonard S, Gault J, Hopkins J et al (2002) Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 59:1085–1096

    Article  PubMed  CAS  Google Scholar 

  • Martin-Ruiz CM, Haroutunian VH, Long P et al (2003) Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia. Biol Psychiatry 54:1222–1233

    Article  PubMed  CAS  Google Scholar 

  • Marutle A, Zhang X, Court J et al (2001) Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat 22:115–126

    Article  PubMed  CAS  Google Scholar 

  • Mathew SV, Law AJ, Lipska BK et al (2007) {alpha}7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in Neuregulin 1. Hum Mol Genet 16:2921–2932

    Article  PubMed  CAS  Google Scholar 

  • McCreadie RG (2002) Use of drugs, alcohol and tobacco by people with schizophrenia: case–control study. Br J Psychiatry 181:321–325

    Article  PubMed  Google Scholar 

  • McGehee DS, Role LW (1995) Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol 57:521–546

    Article  PubMed  CAS  Google Scholar 

  • Pärna K, Rahu M, Youngman LD et al (2005) Self-reported and serum cotinine-validated smoking in pregnant women in Estonia. Matern Child Health J 9:385–392

    Article  PubMed  Google Scholar 

  • Perl O, Ilani T, Strous RD et al (2003) The alpha7 nicotinic acetylcholine receptor in schizophrenia: decreased mRNA levels in peripheral blood lymphocytes. FASEB J 17:1948–1950

    PubMed  CAS  Google Scholar 

  • Perl O, Strous RD, Dranikov A et al (2006) Low levels of alpha7-nicotinic acetylcholine receptor mRNA on peripheral blood lymphocytes in schizophrenia and its association with illness severity. Neuropsychobiology 53:88–93

    Article  PubMed  CAS  Google Scholar 

  • Raux G, Bonnet-Brilhault F, Louchart S et al (2002) The -2 bp deletion in exon 6 of the ‘alpha 7-like’ nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. Mol Psychiatry 7:1006–1011

    Article  PubMed  CAS  Google Scholar 

  • Razani-Boroujerdi S, Boyd RT, Dávila-García MI et al (2007) T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response. J Immunol 179:2889–2898

    PubMed  CAS  Google Scholar 

  • Riley B, Williamson M, Collier D et al (2002) A 3-Mb map of a large segmental duplication overlapping the alpha7-nicotinic acetylcholine receptor gene (CHRNA7) at human 15q13–q14. Genomics 79:197–209

    Article  PubMed  CAS  Google Scholar 

  • Sato KZ, Fujii T, Watanabe Y et al (1999) Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. Neurosci Lett 266:17–20

    Article  PubMed  CAS  Google Scholar 

  • Severance EG, Yolken RH (2008) Novel alpha7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia. Genes Brain Behav 7:37–45

    PubMed  CAS  Google Scholar 

  • Skok MV, Kalashnik EN, Koval LN et al (2003) Functional nicotinic acetylcholine receptors are expressed in B lymphocyte-derived cell lines. Mol Pharmacol 64:885–889

    Article  PubMed  CAS  Google Scholar 

  • Skok MV, Grailhe R, Changeux JP (2005) Nicotinic receptors regulate B lymphocyte activation and immune response. Eur J Pharmacol 517:246–251

    Article  PubMed  CAS  Google Scholar 

  • Takahashi HK, Iwagaki H, Hamano R et al (2007) The immunosuppressive effects of nicotine during human mixed lymphocyte reaction. Eur J Pharmacol 559:69–74

    Article  PubMed  CAS  Google Scholar 

  • Twardella D, Küpper-Nybelen J, Rothenbacher D et al (2004) Short-term benefit of smoking cessation in patients with coronary heart disease: estimates based on self-reported smoking data and serum cotinine measurements. Eur Heart J 25:2101–2108

    Article  PubMed  Google Scholar 

  • Villiger Y, Szanto I, Jaconi S et al (2002) Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. J Neuroimmunol 126:86–98

    Article  PubMed  CAS  Google Scholar 

  • Ziedonis DM, Williams JM (2003) Management of smoking in people with psychiatric disorders. Curr Opin Psychiatry 16:305–315

    Article  Google Scholar 

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Acknowledgments

The authors thank Vada and Theodore Stanley and the Stanley Medical Research Institute for their support. The authors also thank Ann Cusic for administrative assistance.

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Correspondence to Emily G. Severance.

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Severance, E.G., Dickerson, F.B., Stallings, C.R. et al. Differentiating nicotine- versus schizophrenia-associated decreases of the α7 nicotinic acetylcholine receptor transcript, CHRFAM7A, in peripheral blood lymphocytes. J Neural Transm 116, 213–220 (2009). https://doi.org/10.1007/s00702-008-0164-y

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