Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity
Open accessAbstract
Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.
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CB1R antagonism increases BLA excitability, activates the HPA axis, and increases anxiety-like behavior.
“First, presumably by removing AEA-mediated tonic inhibitory activity, CB1R antagonism increases BLA excitability [61–63], activates the hypothalamic–pituitary–adrenal (HPA) axis and increases anxiety-like behavior [58,64,65].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [62]
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Amygdala FAAH and anandamide: mediating protection and recovery from stress
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- Authors
- Meye, F. J., Trezza, V, Vanderschuren, L. J. M. J., Ramakers, G. M. J., & Adan, R. A. H.
- Affiliations
- University Medical Center Utrecht (NL)
- Roma Tre University (IT)
- Utrecht University (NL)
- Corresponding author
- Adan, R A H
- Venue
- Molecular Psychiatry
- Published
- 2012-10-16
- Volume
- 18
- Issue
- 12
- Pages
- 1294-1301
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2095411357
- Cited by
- 76
- References
- 51
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 9 · 2016: 11 · 2015: 7 · 2014: 5 · 2013: 9 · 2012: 1
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Iris (Roma Tre University) (submittedVersion)
- Funders
- Top Institute Pharma
- National Institute of Mental Health
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- cannabinoid 1 receptor, inverse agonists, rimonabant, obesity treatment, constitutive receptor activity, ventral tegmental area, basolateral amygdala, GABAergic neurotransmission, glutamatergic neurotransmission, anxiety, reward motivation, drug safety, weight gain, dietary intake
- MeSH terms
- Rimonabant, Amygdala, Animals, Anxiety, Eating, Humans, Male, Mice, Inbred C57BL, Obesity, Piperidines, Pyrazoles, Weight Gain, Rats, Wistar, Ventral Tegmental Area, Receptor, Cannabinoid, CB1, Mice, Rats, Dopaminergic Neurons, GABAergic Neurons
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