Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors
Xavier Viñals, Estefanía Moreno, Laurence Lanfumey, Arnau Cordomí, Antoni Pastor, Rafael de la Torre, Paola Gasperini, Gemma Navarro, Lesley A. Howell, Leonardo Pardo, Carmen Lluís, Enric I. Canela, Peter J. McCormick, Rafaël Maldonado, Patricia Robledo
PLoS Biology July 9, 2015 DOI: 10.1371/journal.pbio.1002194 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | delta9-tetrahydrocannabinol (THC) |
| Topics | Cannabis Serotonin |
| Keywords | Anxiogenic Cannabinoid receptor G protein-coupled receptor Pharmacology Anxiolytic Antagonist Biochemistry |
| Citations | 211 |
| Key points | CB1R and 5-HT2AR form heteromers that mediate THC-induced cognitive impairment, while antinociceptive effects are independent of 5-HT2AR. |
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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 25
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Cites 11
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- Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice Frontiers in Neuroscience 2010
- Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia Translational Psychiatry November 27, 2012
- Serotonin 5‐HT2A receptor activation induces 2‐arachidonoylglycerol release through a phospholipase c‐dependent mechanism Journal of Neurochemistry August 15, 2006
- Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour The International Journal of Neuropsychopharmacology October 14, 2010
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