University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 2A receptors

Viñals, X, Moreno, E, Lanfumey, L, Cordomi, C, Pastor, A, de La Torre, R, Gasperini, P, Howell, LA, Pardo, L, Lluís, C , Canela, E, McCormick, P, Maldonado, R and Robledo, P (2015) Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 2A receptors PLoS Biology, 13 (7), e1002194.

Full text not available from this repository.

Abstract

Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties

Item Type: Article
Subjects : Veterinary Medicine
Authors :
NameEmailORCID
Viñals, XUNSPECIFIEDUNSPECIFIED
Moreno, EUNSPECIFIEDUNSPECIFIED
Lanfumey, LUNSPECIFIEDUNSPECIFIED
Cordomi, CUNSPECIFIEDUNSPECIFIED
Pastor, AUNSPECIFIEDUNSPECIFIED
de La Torre, RUNSPECIFIEDUNSPECIFIED
Gasperini, PUNSPECIFIEDUNSPECIFIED
Howell, LAUNSPECIFIEDUNSPECIFIED
Pardo, LUNSPECIFIEDUNSPECIFIED
Lluís, CUNSPECIFIEDUNSPECIFIED
Canela, EUNSPECIFIEDUNSPECIFIED
McCormick, Pp.mccormick@surrey.ac.ukUNSPECIFIED
Maldonado, RUNSPECIFIEDUNSPECIFIED
Robledo, PUNSPECIFIEDUNSPECIFIED
Date : 9 July 2015
Identification Number : 10.1371/journal.pbio.1002194
Copyright Disclaimer : Copyright: © 2015 Viñals et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:46
Last Modified : 18 May 2017 12:43
URI: http://epubs.surrey.ac.uk/id/eprint/829145

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800