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.

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 PitiéSalpêtrière, Paris, France.