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Mol Neurobiol. 2018 Aug;55(8):6347-6361. doi: 10.1007/s12035-017-0833-7. Epub 2018 Jan 2.

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

Author information

1
Neuropsychiatry and Addictions Institute (INAD) of Parc de Salut Mar, Centro de Investigación Biomédica En Red de Salud Mental G21, Mental Health Research Group, IMIM-Hospital del Mar Research Institute, Barcelona, Spain.
2
Department of Psychiatry, University of Cambridge, Cambridge, UK.
3
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, Barcelona, Spain.
4
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
5
Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain.
6
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
7
Zucker Hillside Hospital, Feinstein Institute for Medical Research, Northwell Health, New York, NY, USA.
8
Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
9
Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101 San Lorenzo Huipulco, Tlalpan, 14370, Mexico City, Mexico.
10
Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
11
Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición, Madrid, Spain.
12
Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain. probledo@imim.es.
13
Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain. probledo@imim.es.

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; Human olfactory neuroepithelium; Progenitor cells

PMID:
29294249
DOI:
10.1007/s12035-017-0833-7
[Indexed for MEDLINE]

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