How Neurons Detect Cannabis

In a paper published today in eLife, researchers at the University of Bristol share new understanding about how cannabinoid receptors (CB1Rs) are controlled in the brain.

The brain contains about 100 billion neurons that are constantly communicating with one another at specialized junctions called synapses. At the synapse, the electrical ‘firing’ of a nerve cell causes the release of chemicals called neurotransmitters from the presynaptic terminals of its axon. These neurotransmitters cross the synapse and bind to receptors at postsynaptic sites on the dendrites of the next nerve cell.

CB1Rs, the proteins that detect the active components of marijuana, help control information flow in the brain by binding molecules called endocannabinoids, which influence brain functions such as pain, appetite, mood, and memory. However, endocannabinoid signaling goes in the reverse direction compared to most neurotransmitters. The ‘receiving’ CB1Rs are located at presynaptic sites on axons, whereas the release sites are at postsynaptic sites on dendrites.

This retrograde signaling activates presynaptic CB1Rs and dampens presynaptic release of other neurotransmitters, which slows brain activity. But in order for CB1Rs to regulate brain function properly, it is essential that they be sent to the right place on the surface of the axon. Until now, very little has been known about how this occurs.

The researchers tracked newly made CB1Rs in nerve cells grown in a dish and found a short region in the protein that targets CB1R to the axon instead of the dendrites. They also discovered that this region stabilizes CB1R at the surface of the axon, making it more available to receive signals from endocannabinoids.

“In recent years there has been tremendous interest in—and controversy about—activation of CB1R by medical marijuana,” says senior author Jeremy Henley of the University of Bristol. “It is becoming increasingly apparent that activation of CB1Rs could be therapeutically useful for a wide range of diseases such as chronic pain, epilepsy, or multiple sclerosis. Understanding the fundamental properties of CB1R is an important basis for future studies exploring the efficacy and optimization of these targeted approaches.”

It is hoped that this increased understanding of how CB1Rs behave in neurons will pave the way for future studies aimed at examining the possible medical uses of marijuana, or other drugs that target CB1Rs, in treating a wide range of disorders.

Image: Cannabinoid receptor 1 is found on the surface of the long, thin axon (yellow), but not the dendrites (purple). Image courtesy of the University of Bristol.