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The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing

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Abstract

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.

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References

  • Ashburner, J., & Friston, K. J. (1999). Nonlinear spatial normalization using basis functions. Human brain Mapping, 7(4), 254–266.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barkus, E. J., Stirling, J., Hopkins, R. S., & Lewis, S. (2006). Cannabis-induced psychosis-like experiences are associated with high schizotypy. Psychopathology, 39(4), 175–178.

    CAS  PubMed  Google Scholar 

  • Batalla, A., Bhattacharyya, S., Yücel, M., Fusar-Poli, P., Crippa, J. A., et al. (2013). Structural and functional imaging studies in chronic Cannabis users: A systematic review of adolescent and adult findings. PLoS One, 8(2), e55821.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berghuis, P., Rajnicek, A. M., Morozov, Y. M., Ross, R. A., Mulder, J., Urbán, G. M., Monory, K., Marsicano, G., Matteoli, M., Canty, A., Irving, A. J., Katona, I., Yanagawa, Y., Rakic, P., Lutz, B., Mackie, K., & Harkany, T. (2007). Hardwiring the brain: Endocannabinoids shape neuronal connectivity. Science., 316(5828), 1212–1216.

    CAS  PubMed  Google Scholar 

  • Bertolino A., Blasi G. (2009) The genetics of schizophrenia. Neuroscience 164 (1):288-299

  • Blasi, G., De Virgilio, C., Papazacharias, A., Taurisano, P., Gelao, B., Fazio, L., Ursini, G., Sinibaldi, L., Andriola, I., Masellis, R., Romano, R., Rampino, A., Di Giorgio, A., Lo Bianco, L., Caforio, G., Piva, F., Popolizio, T., Bellantuono, C., Todarello, O., Kleinman, J. E., Gadaleta, G., Weinberger, D. R., & Bertolino, A. (2013). Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. JAMA Psychiatry., 70(9), 921–930.

    CAS  PubMed  Google Scholar 

  • Bossong, M. G., Jager, G., van Hell, H. H., Zuurman, L., Jansma, J. M., Mehta, M. A., van Gerven, J. M., Kahn, R. S., & Ramsey, N. F. (2012). Effects of Delta9-tetrahydrocannabinol administration on human encoding and recall memory function: A pharmacological FMRI study. Journal of Cognitive Neuroscience, 24, 588–599.

    PubMed  Google Scholar 

  • Callicott, J. H., Bertolino, A., Mattay, V. S., Langheim, F. J., Duyn, J., Coppola, R., Goldberg, T. E., & Weinberger, D. R. (2000). Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cerebral Cortex., 10(11), 1078–1092.

    CAS  PubMed  Google Scholar 

  • Callicott, J. H., Egan, M. F., Mattay, V. S., Bertolino, A., Bone, A. D., Verchinksi, B., & Weinberger, D. R. (2003). Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. American Journal of Psychiatry, 160(4), 709–719.

    Google Scholar 

  • Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., Poulton, R., & Craig, I. W. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: Longitudinal evidence of a gene X environment interaction. Biological Psychiatry, 57(10), 1117–1127.

    CAS  PubMed  Google Scholar 

  • Colantuoni, C., Lipska, B. K., Ye, T., Hyde, T. M., Tao, R., Leek, J. T., Colantuoni, E. A., Elkahloun, A. G., Herman, M. M., Weinberger, D. R., & Kleinman, J. E. (2011). Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature, 478(7370), 519–523.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Colizzi, M., Fazio, L., Ferranti, L., Porcelli, A., Masellis, R., Marvulli, D., Bonvino, A., Ursini, G., Blasi, G., & Bertolino, A. (2015). Functional genetic variation of the cannabinoid receptor 1 and cannabis use interact on prefrontal connectivity and related working memory behavior. Neuropsychopharmacology, 40(3), 640–649.

    CAS  PubMed  Google Scholar 

  • Crane, N. A., Schuster, R. M., Fusar-Poli, P., & Gonzalez, R. (2013). Effects of cannabis on neurocognitive functioning: Recent advances, neurodevelopmental influences, and sex differences. Neuropsychology Review, 23(2), 117–137.

    PubMed  Google Scholar 

  • Di Forti, M., Morgan, C., Dazzan, P., Pariante, C., Mondelli, V., Marques, T. R., Handley, R., Luzi, S., Russo, M., Paparelli, A., Butt, A., Stilo, S. A., Wiffen, B., Powell, J., & Murray, R. M. (2009). High-potency cannabis and the risk of psychosis. British Journal of Psychiatry, 195(6), 488–491.

    Google Scholar 

  • Eisen, M. B., Spellman, P. T., Brown, P. O., & Botstein, D. (1998). Cluster analysis and display of genome-wide expression patterns. Proceedings of the National Academy of Science of the USA, 95(25), 14863–14868.

    CAS  Google Scholar 

  • Fazio, L., Pergola, G., Papalino, M., Di Carlo, P., Monda, A., Gelao, B., Amoroso, N., Tangaro, S., Rampino, A., Popolizio, T., Bertolino, A., & Blasi, G. (2018). Transcriptomic context of DRD1 is associated with prefrontal activity and behavior during working memory. Proceedings of the National Academy of Sciences of the United States of America, 115(21), 5582–5587.

    CAS  PubMed  PubMed Central  Google Scholar 

  • First, M. B., Gibbon, M., Spitzer, R. L., & Williams, J. B. W. (1996). Guide for the structured clinical interview for DSM-IV Axis I disorders-research version. New York: Biometrics Research.

    Google Scholar 

  • Friston, K. J., Williams, S., Howard, R., Frackowiak, R. S., & Turner, R. (1996). Movement-related effects in fMRI time-series. Magnetic Resonance in Medicine, 35(3), 346–355.

    CAS  PubMed  Google Scholar 

  • Fromer, M., Roussos, P., Sieberts, S. K., Johnson, J. S., Kavanagh, D. H., Perumal, T. M., Ruderfer, D. M., Oh, E. C., Topol, A., Shah, H. R., Klei, L. L., Kramer, R., Pinto, D., Gümüş, Z. H., Cicek, A. E., Dang, K. K., Browne, A., Lu, C., Xie, L., Readhead, B., Stahl, E. A., Xiao, J., Parvizi, M., Hamamsy, T., Fullard, J. F., Wang, Y. C., Mahajan, M. C., Derry, J. M., Dudley, J. T., Hemby, S. E., Logsdon, B. A., Talbot, K., Raj, T., Bennett, D. A., De Jager, P. L., Zhu, J., Zhang, B., Sullivan, P. F., Chess, A., Purcell, S. M., Shinobu, L. A., Mangravite, L. M., Toyoshiba, H., Gur, R. E., Hahn, C. G., Lewis, D. A., Haroutunian, V., Peters, M. A., Lipska, B. K., Buxbaum, J. D., Schadt, E. E., Hirai, K., Roeder, K., Brennand, K. J., Katsanis, N., Domenici, E., Devlin, B., & Sklar, P. (2016). Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience, 19(11), 1442–1453.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fukuda, T., Nagashima, S., Abe, T., Kiyonari, H., Inatome, R., & Yanagi, S. (2016). Rescue of CAMDI deletion-induced delayed radial migration and psychiatric behaviors by HDAC6 inhibitor. EMBO reports, 17(12), 1785–1798.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gaiteri, C., Ding, Y., French, B., Tseng, G. C., & Sibille, E. (2014). Beyond modules and hubs: The potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain and Behavior, 13(1), 13–24.

    CAS  Google Scholar 

  • Ganzer, F., Br Ning, S., Kraft, S., Sack, P.-M., & Thomasius, R. (2016). Weighing the evidence: A systematic review on long-term neurocognitive effects of cannabis use in abstinent adolescents and adults. Neuropsychology Review, 26(2), 186–222.

    PubMed  Google Scholar 

  • Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., Nugent 3rd, T. F., Herman, D. H., Clasen, L. S., Toga, A. W., Rapoport, J. L., & Thompson, P. M. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8174–8179.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herkenham, M., Lynn, A. B., Johnson, M. R., Melvin, L. S., de Costa, B. R., & Rice, K. C. (1991). Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. Journal of Neuroscience, 11(2), 563–583.

    CAS  PubMed  Google Scholar 

  • Jacobus, J., & Tapert, S. F. (2014). Effects of cannabis on the adolescent brain. Current Pharmaceutical Design, 20(13), 2186–2193.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koleske, A. J. (2013). Molecular mechanisms of dendrite stability. Nature Reviews Neuroscience, 14(8), 536–550.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lancichinetti, A., & Fortunato, S. (2012). Consensus clustering in complex networks. Scientific Reports, 2, 2012.

    Google Scholar 

  • Lisdahl, K. M., & Price, J. S. (2012). Increased marijuana use and gender predict poorer cognitive functioning in adolescents and emerging adults. Journal of the International Neuropsychological Society, 18(4), 678–688. https://doi.org/10.1017/S1355617712000276.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lisdahl, K. M., Wright, N. E., Kirchner-Medina, C., Maple, K. E., & Shollenbarger, S. (2014). Considering cannabis: The effects of regular cannabis use on neurocognition in adolescents and young adults. Current Addiction Reports, 1(2), 144–156.

    PubMed  PubMed Central  Google Scholar 

  • Lubman, D. I., Cheetham, A., & Yücel, M. (2015). Cannabis and adolescent brain development. Pharmacology & Therapeutics, 148, 1–16.

    CAS  Google Scholar 

  • Monaco, A., Monda, A., Amoroso, N., Bertolino, A., Blasi, G., Di Carlo, P., Papalino, M., Pergola, G., Tangaro, S., & Bellotti, R. (2018). A complex network approach reveals a pivotal substructure of genes linked to schizophrenia. PLoS One, 13(1), e0190110.

    PubMed  PubMed Central  Google Scholar 

  • Meier, M. H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R. S., McDonald, K., Ward, A., Poulton, R., & Moffitt, T. E. (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences of the United States of America, 109(40), E2657–E2664.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meier, M. H., Caspi, A., Danese, A., Fisher, H. L., Houts, R., Arseneault, L., & Moffitt, T. E. (2018). Associations between adolescent cannabis use and neuropsychological decline: A longitudinal co-twin control study. Addiction, 113(2), 257–265.

    PubMed  Google Scholar 

  • Monda A, Amoroso N, Altomare Basile TM, Bellotti R, Bertolino A, Blasi G, Di Carlo P, Fanizzi A, La Rocca M, Maggipinto T, Monaco A, Papalino M, Pergola G, Tangaro S (2017) Topological complex networks properties for Gene Community detection strategy: DRD2 case study. Emergent Complexity from Nonlinearity, in Physics, Engineering and the Life Sciences. Springer, Cham, pp.199–208.

  • Oldfield, R. C. (1971). The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia, 9(1), 97–113.

    CAS  PubMed  Google Scholar 

  • Pergola, G., Di Carlo, P., Andriola, I., Gelao, B., Torretta, S., Attrotto, M. T., Fazio, L., Raio, A., Albergo, D., Masellis, R., Rampino, A., Blasi, G., & Bertolino, A. (2016). Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance. Psychological Medicine, 46(6), 1135–1150.

    CAS  PubMed  Google Scholar 

  • Pergola, G., Di Carlo, P., D'Ambrosio, E., Gelao, B., Fazio, L., Papalino, M., Monda, A., Scozia, G., Pietrangelo, B., Attrotto, M., Apud, J. A., Chen, Q., Mattay, V. S., Rampino, A., Caforio, G., Weinberger, D. R., Blasi, G., & Bertolino, A. (2017). DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia. Translational Psychiatry, 7(1), e1006.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British Journal of Pharmacology, 153(2), 199–215.

    CAS  PubMed  Google Scholar 

  • SalthouseTA, A. T. M., & Berish, D. E. (2003). Executive functioning as a potential mediator of age-related cognitive decline in normal adults. Journal of Experimental Psychology: General, 132(4), 566–594.

    Google Scholar 

  • Schwarz Gideon, E. (1978). Estimating the dimension of a model. Annals of Statistics, 6(2), 461–464.

    Google Scholar 

  • Snodgrass, J. G., & Corwin, J. (1988). Pragmatics of measuring recognition memory: Applications to dementia and amnesia. Journal of Experimental Psychology: General, 117, 34–50.

    CAS  Google Scholar 

  • Sobell, L. C., Agrawal, S., Annis, H., Ayala-Velazquez, H., Echeverria, L., Leo, G. I., et al. (2001). Cross-cultural evaluation of two drinking assessment instruments: Alcohol timeline followback and inventory of drinking situations. Substance Use & Misuse, 36(3), 313–331.

    CAS  Google Scholar 

  • Sobell, L. C., Agrawal, S., Sobell, M. B., Leo, G. I., Young, L. J., Cunningham, J. A., & Simco, E. R. (2003). Comparison of a quick drinking screen with the timeline followback for individuals with alcohol problems. Journal of Studies on Alcohol, 64(6), 858–861.

    PubMed  Google Scholar 

  • Taurisano, P., Antonucci, L. A., Fazio, L., Rampino, A., Romano, R., Porcelli, A., Masellis, R., Colizzi, M., Quarto, T., Torretta, S., Di Giorgio, A., Pergola, G., Bertolino, A., & Blasi, G. (2016). Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use. Cortex, 81, 231–238.

    PubMed  Google Scholar 

  • van Os, J., Kenis, G., & Rutten, B. P. (2010). The environment and schizophrenia. Nature., 468(7321), 203–212.

    PubMed  Google Scholar 

  • Wong, D. F., Kuwabara, H., Horti, A. G., Raymont, V., Brasic, J., Guevara, M., Ye, W., Dannals, R. F., Ravert, H. T., Nandi, A., Rahmim, A., Ming, J. E., Grachev, I., Roy, C., & Cascella, N. (2010). Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage, 52(4), 1505–1513.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang B, Horvath S (2005). A general framework for weighted gene co-expression network analysis. Statistical Applications in General and Molecular Biology 4: Article17.

  • Zoghbi, H. Y. (2003). Postnatal neurodevelopmental disorders: Meeting at the synapse? Science., 302(5646), 826–830.

    CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Dr. Grazia Caforio, Dr. Marco Colizzi, Dr. Leonardo Fazio, Dr. Barbara Gelao and Dr. Tiziana Quarto, for making data acquisition possible and for the fruitful discussion on the topic of this work. Moreover, we would like to acknowledge all people who participated in this study.

Funding

This research has been partly funded by the “Capitale Umano ad Alta Qualificazione” grant by Fondazione Con Il Sud (2011-PDR-06), by a NARSAD grant (28935), by a Ricerca Finalizzata grant (PE-2011-02347951) awarded to Alessandro Bertolino, and by a Hoffmann-La Roche collaboration grant titled “Gene co-expression networks as roadmap for genotype to phenotype mapping in schizophrenia” awarded to Giulio Pergola. Giulio Pergola’s position is funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant (No. 798181). This article reflects only the authors’ views, and the European Union and Research Executive Agency are not liable for any use that may be made of the information contained therein.

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Authors and Affiliations

  1. Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari – ‘Aldo Moro’, Piazza Giulio Cesare, 11, 70124, Bari, Italy

    Paolo Taurisano, Giulio Pergola, Anna Monda, Linda A. Antonucci, Pasquale Di Carlo, Francesco Piarulli, Roberta Passiatore, Marco Papalino, Raffaella Romano, Antonio Rampino, Aurora Bonvino, Annamaria Porcelli, Alessandro Bertolino & Giuseppe Blasi

  2. IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Foggia, Italy

    Paolo Taurisano & Teresa Popolizio

  3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    Giulio Pergola

  4. Department of Educational Sciences, Psychology and Communication Science, University of Bari – ‘Aldo Moro’, Bari, Italy

    Linda A. Antonucci

  5. INFN, Sezione di Bari, Via A. Orabona 4, 70125, Bari, Italy

    Alfonso Monaco & Roberto Bellotti

  6. Department of Psychiatry, Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy

    Antonio Rampino, Alessandro Bertolino & Giuseppe Blasi

  7. Dipartimento Interateneo di Fisica ‘M. Merlin’, Università degli Studi di Bari ‘Aldo Moro’, Via G.Amendola 173, 70126, Bari, Italy

    Roberto Bellotti

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  1. Paolo Taurisano
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Correspondence to Giuseppe Blasi.

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All procedures performed in this study involving human participants have been approved by the University of Bari ethic committee and comply with the 1964 Helsinki declaration, its later amendments and comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

Giuseppe Blasi received lecture fees from Jannsen and Lundbeck. Alessandro Bertolino is a stockholder of Hoffmann-La Roche Ltd. He has also received consulting fees from Biogen and lecture fees from Otsuka, Janssen, Lundbeck. Giulio Pergola has been the academic supervisor of a Roche collaboration grant (years 2015–16) that funded his and Antonio Rampino’s salary. Antonio Rampino has received travel fees from Lundbeck. All other authors have no biomedical financial interests and no potential conflicts of interest.

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Taurisano, P., Pergola, G., Monda, A. et al. The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing. Brain Imaging and Behavior 15, 288–299 (2021). https://doi.org/10.1007/s11682-020-00256-z

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