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Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity

Molecular Psychiatry volume 18, pages 1294–1301 (2013)Cite this article

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Abstract

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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Acknowledgements

We thank Top Institute Pharma (D1-105) for funding this project. We also thank the NIMH Chemical Synthesis and Drug Supply Program for supplying rimonabant for the purposes of this study. Finally, we would like to thank Prof Ad IJzerman, Prof Bert Leufkens, Dr Mario van der Stelt and Dr Lex van der Ploeg for helpful suggestions on the paper.

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands

    F J Meye, V Trezza, L J M J Vanderschuren, G M J Ramakers & R A H Adan

  2. Department of Biology, University ‘Roma Tre’, Rome, Italy

    V Trezza

  3. Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

    L J M J Vanderschuren

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  1. F J Meye
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Correspondence to R A H Adan.

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Meye, F., Trezza, V., Vanderschuren, L. et al. Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity. Mol Psychiatry 18, 1294–1301 (2013). https://doi.org/10.1038/mp.2012.145

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Keywords

  • cannabinoid 1 receptor
  • constitutive activity
  • inverse agonist
  • mesolimbic dopamine system
  • obesity

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