Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors.
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Endocannabinoid signaling in the dorsal raphe (DR) has recently been implicated in the regulation of anxiety and depression. However, the cellular mechanisms by which endocannabinoids (eCBs) regulate the excitability of DR 5-hydroxytryptamine (serotonin; 5-HT) neurons remain poorly understood. In the present study, using whole-cell recording from DR 5-HT neurons, we examined the effects of eCBs on glutamatergic synapses in the DR. We found that the eCB anandamide decreased the amplitude of evoked excitatory postsynaptic currents (eEPSCs). This effect was blocked by CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251) and mimicked by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2), a CB(1) receptor agonist. The inhibition of eEPSC amplitude was associated with an increase in the paired-pulse ratio and coefficient of variance. Activation of CB(1) receptors also reduced the frequency, but not the amplitude, of miniature excitatory postsynaptic currents, indicating that eCBs inhibit glutamate release in the DR. In addition, we found that depolarization of DR 5-HT neurons induced a transient inhibition of the amplitude of eEPSCs, termed depolarization-induced suppression of excitation (DSE). The induction of DSE required an increase in postsynaptic intracellular calcium and was due to a decrease in glutamate release. Furthermore, pharmacological studies showed that blockade of CB(1) receptors with AM 251 abolished the DSE. In contrast, activation of CB(1) receptors with WIN 55,212-2 mimicked and occluded the DSE, indicating that depolarization of DR 5-HT neurons triggers eCB release, which in turn mediates the DSE. Together, these results indicate that eCBs play a role in modulating glutamatergic synaptic transmission to DR 5-HT neurons.
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AM251 competitively inhibits endocannabinoid activation of CB1 receptors.
“Because AM251 competitively inhibits endocannabinoid activation of CB1 receptors [18]”
From Endocannabinoid involvement in endometriosis. (2010) · cites this paper as [18]
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- Authors
- Haj-Dahmane, S., & Shen, R.-Y.
- Affiliations
- University at Buffalo, State University of New York (US)
- ORCID
- Shen, Roh-Yu
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 331
- Issue
- 1
- Pages
- 186-196
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC2766225
- OpenAlex
- W2132000187
- Cited by
- 69
- References
- 57
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 8 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 1 · 2015: 5 · 2014: 5 · 2013: 6 · 2012: 9
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (AA12435, R01AA012435)
- National Institute of Mental Health (MH078009, R01MH078009)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- CB1 receptor, dorsal raphe nucleus, serotonergic neurons, glutamatergic synapses, excitatory postsynaptic currents, anandamide, glutamate release, presynaptic inhibition, anxiety, depression
- MeSH terms
- Animals, Male, Neural Inhibition, Synaptic Transmission, Neurons, Raphe Nuclei, Serotonin, Rats, Sprague-Dawley, Receptors, Presynaptic, Presynaptic Terminals, Excitatory Postsynaptic Potentials, Receptor, Cannabinoid, CB1, Rats, Cannabinoid Receptor Modulators, Endocannabinoids
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