ArticlePLoS biology2015
Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.
Article in PLoS biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
94 citing papers in PubMed, 2 syntheses or guidelines pooled it, 204 citations in OpenAlex.
- The Autism-Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System.International journal of environmental research and public health · 2022Pooled it
- Highway to hell or magic smoke? The dose-dependence of ΔLearning & memory (Cold Spring Harbor, N.Y.) · 2018Pooled it
- Adolescents are more sensitive than adults to acute behavioral and cognitive effects of THC.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Trial
- Mechanistic and therapeutic insights into class A GPCR dimers in neuropsychiatric disorders.npj drug discovery · 2026Review
- Memory impairment and chronic high-dose Δ9-THC/cannabis exposure: a narrative review of molecular mechanisms underlying neurotoxic effects.Psychopharmacology · 2026Review
- Article
- β2-Adrenergic Receptor Utilizes Distinct Interaction Interfaces to Selectively form Heterooligomers with a Subset of Bitter Taste Receptors.Biochemistry · 2025Article
- In Vitro Signaling Properties of Cannabinoid and Orexin Receptors: How Orexin Receptors Influence Cannabinoid Receptor-Mediated Signaling.Pharmacology research & perspectives · 2025Article
- Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CBJournal of medicinal chemistry · 2025Article
- Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI.Acta neuropathologica communications · 2024Article
- Centralizing the Knowledge and Interpretation of Pain in Chemotherapy-Induced Peripheral Neuropathy: A Paradigm Shift towards Brain-Centric Approaches.Brain sciences · 2024Review
- G protein-specific mechanisms in the serotonin 5-HTNature communications · 2024Article
- Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey.Pharmaceuticals (Basel, Switzerland) · 2024Review
- The CBEMBO molecular medicine · 2024Article
- Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HTNeurochemical research · 2024Article
- The Effects of Psychedelics on Neuronal Physiology.Annual review of physiology · 2024Review
- Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders.International journal of molecular sciences · 2023Review
- Cognitive Alterations in Addictive Disorders: A Translational Approach.Biomedicines · 2023Review
- The effects of serotonergic psychedelics in synaptic and intrinsic properties of neurons in layer II/III of the orbitofrontal cortex.Psychopharmacology · 2023Article
- The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death.Cellular and molecular neurobiology · 2023Review
34 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.