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Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography

  • Author Footnotes
    1 JH and PZ-F contributed equally to this work.
    Jussi Hirvonen
    Correspondence
    Address correspondence to Jussi Hirvonen, M.D., Ph.D., Department of Radiology and Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FIN-20520, Turku, Finland.
    Footnotes
    1 JH and PZ-F contributed equally to this work.
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

    Department of Radiology, University of Turku, Turku, Finland
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  • Author Footnotes
    1 JH and PZ-F contributed equally to this work.
    Paolo Zanotti-Fregonara
    Footnotes
    1 JH and PZ-F contributed equally to this work.
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

    Houston Methodist Research Institute, Houston, Texas
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  • David A. Gorelick
    Affiliations
    Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

    Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland
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  • Chul Hyoung Lyoo
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Denise Rallis-Frutos
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Cheryl Morse
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Sami S. Zoghbi
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Victor W. Pike
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Nora D. Volkow
    Affiliations
    Office of the Director, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
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  • Marilyn A. Huestis
    Affiliations
    Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

    Lambert Center for the Study of Medicinal Cannabis and Hemp, Thomas Jefferson University, Philadelphia, Pennsylvania
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  • Robert B. Innis
    Affiliations
    Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Author Footnotes
    1 JH and PZ-F contributed equally to this work.

      Abstract

      Background

      Previous studies showed reduction of brain cannabinoid CB1 receptors in adults with cannabis and alcohol use disorders. Preclinical data suggest that these receptors also contribute to nicotine reward and dependence. Tobacco smoking may confound clinical studies of psychiatric disorders because many patients with such disorders smoke tobacco. Whether human subjects who smoke tobacco but are otherwise healthy have altered CB1 receptor binding in brain is unknown.

      Methods

      We measured CB1 receptors in brains of 18 healthy men who smoke tobacco (frequent chronic cigarette smokers), and 28 healthy men who do not smoke tobacco, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We collected arterial blood samples during scanning to calculate the distribution volume (VT), which is nearly proportional to CB1 receptor density. Repeated-measures analysis of variance compared VT between groups in various brain regions.

      Results

      Brain CB1 receptor VT was about 20% lower in subjects who smoke tobacco than in subjects who do not. Decreased VT was found in all brain regions, but reduction did not correlate with years of smoking, number of cigarettes smoked per day, or measures of nicotine dependence.

      Conclusions

      Tobacco-smoking healthy men have a widespread reduction of CB1 receptor density in brain. Reduction of CB1 receptors appears to be a common feature of substance use disorders. Future clinical studies on the CB1 receptor should control for tobacco smoking.

      Keywords

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      References

        • Parsons L.H.
        • Hurd Y.L.
        Endocannabinoid signalling in reward and addiction.
        Nat Rev Neurosci. 2015; 16: 579-594
        • Martin C.S.
        • Clifford P.R.
        • Maisto S.A.
        • Earleywine M.
        • Kirisci L.
        • Longabaugh R.
        Polydrug use in an inpatient treatment sample of problem drinkers.
        Alcohol Clin Exp Res. 1996; 20: 413-417
        • Herkenham M.
        • Lynn A.B.
        • Little M.D.
        • Johnson M.R.
        • Melvin L.S.
        • de Costa B.R.
        • Rice K.C.
        Cannabinoid receptor localization in brain.
        Proc Natl Acad Sci U S A. 1990; 87: 1932-1936
        • Vries T.
        • Schoffelmeer A.
        Cannabinoid CB receptors control conditioned drug seeking.
        Trends Pharmacol Sci. 2005; 26: 420-426
        • Terry G.E.
        • Hirvonen J.
        • Liow J.S.
        • Zoghbi S.S.
        • Gladding R.
        • Tauscher J.T.
        • et al.
        Imaging and quantitation of cannabinoid CB1 receptors in human and monkey brains using 18F-labeled inverse agonist radioligands.
        J Nucl Med. 2010; 51: 112-120
        • Donohue S.R.
        • Krushinski J.H.
        • Pike V.W.
        • Chernet E.
        • Phebus L.
        • Chesterfield A.K.
        • et al.
        Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.
        J Med Chem. 2008; 51: 5833-5842
        • Hirvonen J.
        • Goodwin R.S.
        • Li C.T.
        • Terry G.E.
        • Zoghbi S.S.
        • Morse C.
        • et al.
        Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.
        Mol Psychiatry. 2012; 17: 642-649
        • Hirvonen J.
        • Zanotti-Fregonara P.
        • Umhau J.C.
        • George D.T.
        • Rallis-Frutos D.
        • Lyoo C.H.
        • et al.
        Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography.
        Mol Psychiatry. 2013; 18: 916-921
        • Gamaleddin I.H.
        • Trigo J.M.
        • Gueye A.B.
        • Zvonok A.
        • Makriyannis A.
        • Goldberg S.R.
        • Le Foll B.
        Role of the endogenous cannabinoid system in nicotine addiction: Novel insights.
        Front Psychiatry. 2015; 6: 41
        • Cahill K.
        • Ussher M.H.
        Cannabinoid type 1 receptor antagonists for smoking cessation.
        Cochrane Database Syst Rev. 2011; 3: CD005353
        • Robinson J.D.
        • Cinciripini P.M.
        • Karam-Hage M.
        • Aubin H.J.
        • Dale L.C.
        • Niaura R.
        • et al.
        Pooled analysis of three randomized, double-blind, placebo controlled trials with rimonabant for smoking cessation.
        Addict Biol. 2018; 23: 291-303
        • Gandelman M.S.
        • Baldwin R.M.
        • Zoghbi S.S.
        • Zea-Ponce Y.
        • Innis R.B.
        Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: Beta-CIT, IBF, and iomazenil.
        J Pharm Sci. 1994; 83: 1014-1019
        • Zoghbi S.S.
        • Shetty H.U.
        • Ichise M.
        • Fujita M.
        • Imaizumi M.
        • Liow J.S.
        • et al.
        PET imaging of the dopamine transporter with 18F-FECNT: A polar radiometabolite confounds brain radioligand measurements.
        J Nucl Med. 2006; 47: 520-527
        • Tzourio-Mazoyer N.
        • Landeau B.
        • Papathanassiou D.
        • Crivello F.
        • Etard O.
        • Delcroix N.
        • et al.
        Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
        NeuroImage. 2002; 15: 273-289
        • Burger C.
        • Mikolajczyk K.
        • Grodzki M.
        • Rudnicki P.
        • Szabatin M.
        • Buck A.
        Java tools for quantitative post-processing of brain PET data.
        J Nucl Med. 1998; 39: 277p-278p
        • Friston K.J.
        • Holmes A.P.
        • Worsley K.J.
        • Poline J.P.
        • Frith C.
        • Frackowiak R.S.J.
        Statistical parametric maps in functional imaging: A general linear approach.
        Hum Brain Mapp. 1995; 2: 189-210
        • Innis R.B.
        • Cunningham V.J.
        • Delforge J.
        • Fujita M.
        • Gjedde A.
        • Gunn R.N.
        • et al.
        Consensus nomenclature for in vivo imaging of reversibly binding radioligands.
        J Cereb Blood Flow Metab. 2007; 27: 1533-1539
        • Aydin C.
        • Oztan O.
        • Isgor C.
        Long-term effects of juvenile nicotine exposure on abstinence-related social anxiety-like behavior and amygdalar cannabinoid receptor 1 (CB1R) mRNA expression in the novelty-seeking phenotype.
        Behav Brain Res. 2012; 228: 236-239
        • Mateos B.
        • Borcel E.
        • Loriga R.
        • Luesu W.
        • Bini V.
        • Llorente R.
        • et al.
        Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long-lasting memory impairments and changes in brain nicotinic and CB1 cannabinoid receptors.
        J Psychopharmacol. 2011; 25: 1676-1690
        • Marco E.M.
        • Granstrem O.
        • Moreno E.
        • Llorente R.
        • Adriani W.
        • Laviola G.
        • Viveros M.P.
        Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats.
        Eur J Pharmacol. 2007; 557: 37-43
        • Werling L.L.
        • Reed S.C.
        • Wade D.
        • Izenwasser S.
        Chronic nicotine alters cannabinoid-mediated locomotor activity and receptor density in periadolescent but not adult male rats.
        Int J Dev Neurosci. 2009; 27: 263-269
        • Gonzalez S.
        • Fernandez-Ruiz J.
        • Sparpaglione V.
        • Parolaro D.
        • Ramos J.A.
        Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB1 receptor binding and mRNA levels.
        Drug Alcohol Depend. 2002; 66: 77-84
        • Balerio G.N.
        • Aso E.
        • Berrendero F.
        • Murtra P.
        • Maldonado R.
        Delta9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice.
        Eur J Neurosci. 2004; 20: 2737-2748
        • Gérard N.
        • Ceccarini J.
        • Bormans G.
        • Vanbilloen B.
        • Casteels C.
        • Goffin K.
        • et al.
        Influence of chronic nicotine administration on cerebral type 1 cannabinoid receptor binding: An in vivo micro-PET study in the rat using [18F]MK-9470.
        J Mol Neurosci. 2010; 42: 162-167
        • Hirvonen J.
        In vivo imaging of the cannabinoid CB1 receptor with positron emission tomography.
        Clin Pharmacol Ther. 2015; 97: 565-567
        • Caille S.
        • Alvarez-Jaimes L.
        • Polis I.
        • Stouffer D.G.
        • Parsons L.H.
        Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration.
        J Neurosci. 2007; 27: 3695-3702
        • Ranganathan M.
        • Cortes-Briones J.
        • Radhakrishnan R.
        • Thurnauer H.
        • Planeta B.
        • Skosnik P.
        • et al.
        Reduced brain cannabinoid receptor availability in schizophrenia.
        Biol Psychiatry. 2016; 79: 997-1005
        • Pavon F.J.
        • Serrano A.
        • Sidhpura N.
        • Polis I.
        • Stouffer D.
        • de Fonseca F.R.
        • et al.
        Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens.
        Addict Biol. 2018; 23: 723-734
        • Cheer J.F.
        • Wassum K.M.
        • Sombers L.A.
        • Heien M.L.A.V.
        • Ariansen J.L.
        • Aragona B.J.
        • et al.
        Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation.
        J Neurosci. 2007; 27: 791-795
        • Buczynski M.W.
        • Polis I.Y.
        • Parsons L.H.
        The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area.
        Neuropsychopharmacology. 2013; 38: 574-584
        • Terry G.
        • Liow J.
        • Chernet E.
        • Zoghbi S.
        • Phebus L.
        • Felder C.
        • et al.
        Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents.
        NeuroImage. 2008; 41: 690-698
        • Rossi S.
        • De Chiara V.
        • Musella A.
        • Mataluni G.
        • Sacchetti L.
        • Siracusano A.
        • et al.
        Effects of caffeine on striatal neurotransmission: Focus on cannabinoid CB1 receptors.
        Mol Nutr Food Res. 2010; 54: 525-531

      Linked Article

      • The Importance of Drug and Sex Effects in Psychiatric Research
        Biological PsychiatryVol. 84Issue 10
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          Rates of tobacco smoking are disproportionately higher among people with major psychiatric diagnoses and other substance use disorders. This disparity is an important aspect to improving public health. It is therefore critical that we consider tobacco smoking in human research of psychiatric disorders. The article by Hirvonen et al. (1) in this issue of Biological Psychiatry addresses this consideration by measuring cannabinoid 1 (CB1) receptor availability in healthy male tobacco smokers compared with healthy male nonsmokers.
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