Study Identifies Molecular Mechanism Behind Cannabinoid Tolerance
- Researchers discovered that long-term cannabinoid tolerance in mice is driven by a cellular process where repeated activation of CB1 receptors leads to their breakdown and reduced abundance in the brain.
- The enzyme NEDD4L was identified as key in this process, tagging CB1 receptors with ubiquitin molecules that mark them for degradation, lowering receptor levels in neurons.
- Preventing this degradation process stabilized CB1 receptor levels and eliminated behavioral cannabinoid tolerance in mice, without affecting their acute cannabinoid responses.
- These findings provide a potential foundation for future treatments to limit cannabinoid tolerance, although further research is needed to confirm if the mechanism applies to humans.
(Photo credit: PBS).
Researchers have identified a molecular process that appears to drive long-term cannabinoid tolerance in mice, offering new insight into why repeated exposure to cannabinoids can produce progressively weaker effects.
The study, published in the Proceedings of the National Academy of Sciences, found that repeated activation of cannabinoid CB1 receptors triggers a cellular process that causes the receptors to be broken down, reducing their abundance in the brain.
CB1 receptors are a primary target of THC and other cannabinoids and are responsible for many of marijuana’s effects on the brain. While scientists have long known that repeated cannabinoid exposure can cause CB1 receptors to become less responsive or decline in number, the mechanisms responsible for longer-term tolerance have remained less clear.
Researchers identified an enzyme known as NEDD4L as a key part of the process. Cannabinoid activation set off a signaling pathway that activated NEDD4L, which then attached ubiquitin molecules to four specific sites on the CB1 receptor. Ubiquitin functions partly as a cellular tag that can mark proteins for removal.
Once tagged, the CB1 receptors were targeted for degradation, reducing receptor levels in neurons both in laboratory experiments and in the brains of mice.
Researchers then used several approaches to prevent the CB1 receptors from undergoing this process. Doing so stabilized receptor levels and eliminated behavioral cannabinoid tolerance in the mice, while leaving the animals’ acute responses to cannabinoids intact.
The findings suggest that NEDD4L-mediated degradation of CB1 receptors may be a central mechanism behind cannabinoid tolerance, according to the researchers.
Tolerance can be particularly relevant for patients using cannabinoid-based medicines over extended periods, as increasingly weaker responses can reduce therapeutic effectiveness. The researchers said understanding how CB1 receptor levels are regulated could provide a foundation for future approaches designed to limit tolerance.
The study was conducted by researchers affiliated with Complutense University of Madrid, the University of Bordeaux and other research institutions in Spain and France. It was published online August 25.
Because the experiments involved cells and mice rather than human marijuana consumers, the findings do not establish that blocking the same pathway would prevent tolerance in people. Additional research would be needed to determine whether the mechanism could eventually have clinical applications.