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Molecular Neurobiology

, Volume 55, Issue 8, pp 6347–6361 | Cite as

Cannabis Users Show Enhanced Expression of CB1-5HT2A Receptor Heteromers in Olfactory Neuroepithelium Cells

  • Liliana Galindo
  • Estefanía Moreno
  • Fernando López-Armenta
  • Daniel Guinart
  • Aida Cuenca-Royo
  • Mercè Izquierdo-Serra
  • Laura Xicota
  • Cristina Fernandez
  • Esther Menoyo
  • José M. Fernández-Fernández
  • Gloria Benítez-King
  • Enric I. Canela
  • Vicent Casadó
  • Víctor Pérez
  • Rafael de la Torre
  • Patricia Robledo
Article

Abstract

Cannabinoid CB1 receptors (CB1R) and serotonergic 2A receptors (5HT2AR) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB1R-5HT2AR heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na+ currents in patch clamp recordings. Interestingly, CB1R-5HT2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

Keywords

CB1R-5HT2AR heteromers Cannabis Cognitive Progenitor cells Human olfactory neuroepithelium 

Notes

Acknowledgments

This work was supported by grants from DIUE de la Generalitat de Catalunya (2014-SGR-680 and 2014-SGR-1236 to RTF), Instituto de Salud Carlos III, (P14/00210 to P.R.) FIS-FEDER Funds, Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; grant SAF-2014-54840-R to E.I.C. and V.C., grant SAF-2015-69762-R to J.M.F-F., grant MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to Department of Experimental and Health Sciences), and the following networks of Instituto de Salud Carlos III: Red de Trastornos Adictivos, CIBER de Salud Mental, CIBER de Fisiopatología de la Obesidad y Nutrición and CIBER de Enfermedades Neurodegenerativas. M.I.-S. holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness. We would like to thank Dr. María Inmaculada Hernández Muñoz for providing the primers in our gene expression studies and for her invaluable comments and suggestions, Klaus Langohr for his help with the statistical analyses, and Jordi García and Mitona Pujadas for excellent technical assistance. Laura Xicota is currently at ICM Institut du Cerveau et de la Moelle épinière (CNRS UMR7225, INSERM U1127, UPMC) Hôpital de la Pitié-Salpêtrière, Paris, France.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2017_833_MOESM1_ESM.docx (27 kb)
Supp. Table 1 (DOCX 26 kb)
12035_2017_833_MOESM2_ESM.docx (27 kb)
Supp. Table 2 (DOCX 26 kb)
12035_2017_833_MOESM3_ESM.docx (26 kb)
Supp. Table 3 (DOCX 26 kb)
12035_2017_833_MOESM4_ESM.docx (7.7 mb)
Supp. Fig. 1 Biochemical experiments in ON cells. (A) Quantification of relative fluorescence of βIII-tubulin and nestin in ON cells from control subjects and cannabis users. (B) Representative immunoblots for βIII-tubulin, nestin, and actin in controls and cannabis users. (C) Quantification of relative protein intensity of β-III tubulin and nestin in ON cells from control subjects (n = 7) and cannabis users (n = 6). (D-E) Representative confocal microscopy images of ON cells in proximity ligation assays for of the control condition in the absence of anti-5HT2AR primary antibody of a control subject (D), and a cannabis user (E). (DOCX 7915 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Liliana Galindo
    • 1
    • 2
  • Estefanía Moreno
    • 3
    • 4
  • Fernando López-Armenta
    • 5
  • Daniel Guinart
    • 1
    • 7
    • 8
  • Aida Cuenca-Royo
    • 5
  • Mercè Izquierdo-Serra
    • 9
  • Laura Xicota
    • 5
  • Cristina Fernandez
    • 5
  • Esther Menoyo
    • 5
  • José M. Fernández-Fernández
    • 9
  • Gloria Benítez-King
    • 10
  • Enric I. Canela
    • 3
    • 4
  • Vicent Casadó
    • 3
    • 4
  • Víctor Pérez
    • 1
  • Rafael de la Torre
    • 5
    • 6
    • 11
  • Patricia Robledo
    • 5
    • 6
  1. 1.Neuropsychiatry and Addictions Institute (INAD) of Parc de Salut Mar, Centro de Investigación Biomédica En Red de Salud Mental G21, Mental Health Research GroupIMIM-Hospital del Mar Research InstituteBarcelonaSpain
  2. 2.Department of PsychiatryUniversity of CambridgeCambridgeUK
  3. 3.Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of BarcelonaUniversity of BarcelonaBarcelonaSpain
  4. 4.Centro de Investigación Biomédica en Red Sobre Enfermedades NeurodegenerativasInstituto de Salud Carlos IIIMadridSpain
  5. 5.Integrative Pharmacology and Systems NeuroscienceIMIM-Hospital del Mar Research InstituteBarcelonaSpain
  6. 6.Department of Experimental and Health SciencesUniversity Pompeu FabraBarcelonaSpain
  7. 7.Department of Psychiatry and Legal MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  8. 8.Zucker Hillside Hospital, Feinstein Institute for Medical ResearchNorthwell HealthNew YorkUSA
  9. 9.Laboratory of Molecular Physiology, Department of Experimental and Health SciencesUniversity Pompeu FabraBarcelonaSpain
  10. 10.Laboratorio de Neurofarmacología, Subdirección de Investigaciones ClínicasInstituto Nacional de Psiquiatría Ramón de la Fuente MuñizMexico CityMexico
  11. 11.Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y NutriciónMadridSpain

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