Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission
Open accessAbstract
It is widely accepted that cannabinoids regulate GABA release by activation of cannabinoid receptor type 1 (CB1). Results obtained from a variety of brain regions consistently indicate that cannabinoid agonists can also reduce glutamatergic synaptic transmission. However, there are still conflicting data concerning the role of CB1 in cannabinoid-induced inhibition of glutamatergic transmission in cortical areas. Here, we provide direct evidence that activation of CB1 on terminals of principal neurons controls excitatory synaptic responses in the forebrain. In slices of the basolateral amygdala, the CA1 region of the hippocampus, and the primary somatosensory cortex of wild-type mice, application of the CB1 agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; WIN) (5 mum) reduced evoked excitatory postsynaptic responses. In contrast, in slices obtained from conditional mouse mutants lacking CB1 in all principal forebrain neurons but not in GABAergic interneurons (CB1(f/f;CaMKIIalphaCre)), WIN no longer affected glutamatergic synaptic transmission in any of the brain regions tested. Compatible with a presynaptic mechanism, WIN did not change the sensitivity to focally uncaged l-glutamate. WIN reduced glutamatergic responses in slices obtained from mice lacking CB1 exclusively in GABAergic neurons (CB1(f/f;Dlx5/6-Cre)), thus excluding the involvement of CB1 expressed on GABAergic neurons in this effect of the drug. The present data strongly indicate that excitatory synaptic transmission in forebrain areas is directly modulated by CB1 expressed on presynaptic axon terminals originating from glutamatergic neurons.
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Activation of CB1R in the BLA causes a decrease in both glutamatergic and GABAergic transmission, with typically a net reduction in neuronal excitability on application of CB1R agonists, probably due to presynaptic inhibition of glutamate release.
“Although activation of CB1R in the BLA causes a decrease in both glutamatergic and GABAergic transmission, there is typically a net reduction in neuronal excitability on application of CB1R agonists, probably due to CB1R-mediated presynaptic inhibition of glutamate release [48,49].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [49]
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- Authors
- Domenici, M. R., Azad, S. C., Marsicano, G., Schierloh, A., Wotjak, C. T., Dodt, H.-U., Zieglgänsberger, W., Lutz, B., & Rammes, G.
- Affiliations
- Max Planck Society (DE)
- Johannes Gutenberg University Mainz (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-05-24
- Volume
- 26
- Issue
- 21
- Pages
- 5794-5799
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675276
- OpenAlex
- W2070956031
- Cited by
- 224
- References
- 37
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 10 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 7 · 2017: 11 · 2016: 12 · 2015: 14 · 2014: 10 · 2013: 10 · 2012: 14
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- cannabinoid receptor type 1, CB1 receptor, presynaptic terminals, glutamatergic neurotransmission, WIN 55,212-2, forebrain, basolateral amygdala, hippocampal CA1, primary somatosensory cortex, principal neurons, GABAergic interneurons, glutamate uncaging
- MeSH terms
- Animals, Cells, Cultured, gamma-Aminobutyric Acid, Synaptic Transmission, Neurons, Prosencephalon, Presynaptic Terminals, Glutamic Acid, Receptor, Cannabinoid, CB1, Mice
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