Cited by 675Cannabis and Cannabinoid ResearchNeuroscience and Neuropharmacology ResearchPharmacological Receptor Mechanisms and Effects

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Multiple Functions of Endocannabinoid Signaling in the Brain

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Katona, István, Freund, Tamás F.·2012·Annual Review of Neuroscience

DOI 10.1146/annurev-neuro-062111-150420PMC PMC4273654

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Abstract

Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical, and physiological characteristics of endocannabinoid signaling has revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then, we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes, thereby differentially governing homeostatic, short-term, and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type– and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids.

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Background
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Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus
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Agonist-Induced Internalization and Trafficking of Cannabinoid CB1Receptors in Hippocampal Neurons
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Widespread Decrease of Type 1 Cannabinoid Receptor Availability in Huntington Disease In Vivo
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Self-citation
Unique inhibitory synapse with particularly rich endocannabinoid signaling machinery on pyramidal neurons in basal amygdaloid nucleus
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Distinct Endocannabinoid Control of GABA Release at Perisomatic and Dendritic Synapses in the Hippocampus
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Retrograde Regulation of GABA Transmission by the Tonic Release of Oxytocin and Endocannabinoids Governs Postsynaptic Firing
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“…receptors OX1 and OX2 (Haj-Dahmane and Shen, 2005), endothelin-1 and its ETA receptor (Zampronio et al., 2010), oxytocin and its OT receptor (Oliet et al., 2007) or ghrelin and its receptor (Kola et al., 2008), and then regulate feed-back hormonal responses via the modification of synaptic…”
Background
A Molecular Basis of Analgesic Tolerance to Cannabinoids
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DAG Lipase Activity Is Necessary for TRP Channel Regulation in Drosophila Photoreceptors
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Postsynaptic diacylglycerol lipase α mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex
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Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB 1 ) receptors in the regenerating liver
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The Endocannabinoid 2-Arachidonoylglycerol Is Responsible for the Slow Self-Inhibition in Neocortical Interneurons
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Activation of PAF receptors results in enhanced synthesis of 2‐arachidonoylglycerol (2‐AG) in immune cells
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AAV Vector-Mediated Overexpression of CB1 Cannabinoid Receptor in Pyramidal Neurons of the Hippocampus Protects against Seizure-Induced Excitoxicity
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Identification of Novel Endogenous Cytochrome P450 Arachidonate Metabolites with High Affinity for Cannabinoid Receptors
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Forebrain-Specific Inactivation of G q /G 11 Family G Proteins Results in Age-Dependent Epilepsy and Impaired Endocannabinoid Formation
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Complementary synaptic distribution of enzymes responsible for synthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in the human hippocampus
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Synaptic activation of kainate receptors gates presynaptic CB1 signaling at GABAergic synapses
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Authors: Katona, I., & Freund, T. F.
Affiliations: HUN-REN Institute of Experimental Medicine (HU)
ORCID: Katona, István
Freund, Tamás F.
Venue: Annual Review of Neuroscience
Publisher: Annual Reviews
Published: 2012-07-21
Volume: 35
Issue: 1
Pages: 529-558
ISSN: 0147-006X (ISSN-L)
1545-4126
DOI: 10.1146/annurev-neuro-062111-150420
PMC: PMC4273654
OpenAlex: W2168499817
Cited by: 630
References: 183
Citations by year: 2026: 39 · 2025: 35 · 2024: 29 · 2023: 44 · 2022: 53 · 2021: 60 · 2020: 56 · 2019: 32 · 2018: 50 · 2017: 57 · 2016: 34 · 2015: 45 · 2014: 43 · 2013: 41 · 2012: 11
FWCI: 5.19
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Annual Review of Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Wellcome Trust (090946)
National Institute of Mental Health (R01MH054671, MH54671)
National Institute of Neurological Disorders and Stroke (R37NS030549, R01NS030549, NS30549)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
Keywords: endocannabinoid signaling, anandamide, 2-arachidonoylglycerol, signalosome, synaptic plasticity, intracellular signaling, cell type-specific signaling, brain
MeSH terms: Animals, Arachidonic Acids, Behavior, Animal, Brain, Glycerides, Humans, Ligands, Models, Neurological, Synaptic Transmission, Neuronal Plasticity, Signal Transduction, Receptors, Cannabinoid, Polyunsaturated Alkamides, Endocannabinoids

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Multiple Functions of Endocannabinoid Signaling in the Brain

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