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Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity
F J Meye1, V Trezza, L J M J Vanderschuren
1Rudolf Magnus Institute, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
Insights
Cannabinoid 1 receptor (CB1R) inverse agonists cause anxiety, unlike neutral antagonists. Both drug types reduce obesity, but neutral CB1R antagonists offer a safer obesity treatment by avoiding negative side effects.
Area of Science:
- Neurobiology
- Pharmacology
- Obesity Research
Background:
- Obesity has significant neurobiological factors, with the cannabinoid 1 receptor (CB1R) identified as a potential drug target.
- Previous CB1R antagonists, like rimonabant, were withdrawn due to adverse psychological effects, including anxiety and suicidality.
Purpose of the Study:
- To investigate the neurobiological underpinnings of constitutive cannabinoid 1 receptor (CB1R) activity.
- To compare the effects of CB1R inverse agonists and neutral antagonists on neurotransmission, mood, motivation, and obesity.
Main Methods:
- Examined constitutive CB1R activity in artificial cell systems and its regulation of neurotransmission in the ventral tegmental area and basolateral amygdala.
- Assessed the effects of the inverse agonist rimonabant and the neutral antagonist NESS0327 on anxiety, motivation, food intake, and weight gain in relevant brain regions.
Main Results:
- Constitutive CB1R activity influences GABAergic and glutamatergic neurotransmission, impacting motivation and emotional regulation.
- CB1R inverse agonists (e.g., rimonabant) suppress constitutive activity, leading to anxiety and reduced reward motivation.
- Neutral CB1R antagonists (e.g., NESS0327) do not affect constitutive activity and lack adverse psychological effects.
- Both rimonabant and NESS0327 demonstrated efficacy in reducing weight gain and food intake.
Conclusions:
- Neutral CB1R antagonists represent a safer and effective therapeutic strategy for obesity treatment compared to inverse agonists.
- Targeting constitutive CB1R activity offers a potential pathway for developing anti-obesity medications with improved safety profiles.
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