Brain Receptors For Cannabis Could Be Why Some People Are More Resilient

A receptor that cannabis latches onto in the brain could be a promising target for future mental health treatments.

Experiencing chronic stress is known to leave people vulnerable to depression or anxiety, and a new study on mice suggests cannabinoid receptors might be the reason some of us show more resilience in the face of overwhelming pressure.

Led by researchers at the University of Laval in Canada, the study found that mice with increased levels of cannabinoid receptor 1 (CB1) on certain brain cells show significantly fewer behaviors associated with anxiety or depression, even when they are subject to chronic social stress.

The results have neuroscientists hypothesizing that CB1, the most common cannabinoid receptor in the brain, may have a protective role to play against two of the most common mental health disorders.

CB1 can be activated by natural neurotransmitters in the body or by cannabis, and among many other crucial bodily functions, it plays a fundamental role in stress responses.

The findings don't necessarily imply that cannabis as a drug can protect the brain from chronic stress, but researchers say it does suggest the possibility of trying similar yet more targeted molecules in future drug trials.

"The challenge, however, is to limit their effects to astrocytes, because strong and prolonged activation of the same receptors in neurons can have side effects, notably on alertness, anxiety and appetite," explains neuroscientist Caroline Ménard, who heads the lab at Laval.

The majority of CB1 receptors in the brain act on neurons, but some of these triggers are also found on non-neuronal cells called astrocytes. Astrocytes are the most common cell in the central nervous system, and recently, they have emerged as key regulators of cognitive function.

The 'feet' of these star-shaped cells press up against blood vessels in the brain, creating a protective barrier through which only certain molecules can flow. According to the new experiments on mice, CB1 receptors play a crucial role in maintaining the integrity of this blood-brain barrier.

Previous studies have found that chronic stress in mice damages the blood-brain barrier, increasing inflammation in the brain and leading to the animals acting in depressed ways.

If the blood-brain barrier is kept intact, however, the depressive-like behaviors, including social avoidance, anhedonia, and anxiety, are reduced.

"We noticed that mice resilient to stress had more CB1 receptors in the barrier than mice with depressive-like behavior or mice not exposed to stress," explains Ménard.

"That gave us the idea to investigate the role of astrocytic CB1 receptors in the response to chronic stress."

Ménard and her colleagues induced some mice brains to over-express CB1 receptors on certain astrocytes. By doing so, the researchers showed they could reduce inflammation in the brain, maintain the integrity of the blood-brain barrier, and hold off symptoms of anxiety and depression, even when they were socially harassed by aggressive mice for days on end.

Physical activity had a remarkably similar effect to the over-expression of CB1 receptors.

Mice that were genetically altered to be missing the genes for this receptor, however, were highly sensitive to stress.

The researchers only altered CB1 expression in two brain regions where the blood-brain barrier seems most vulnerable to stress: the nucleus accumbens – associated with reward and mood regulation – and the prefrontal cortex – associated with social behaviors, decision-making, and executive function.

Upon examining postmortem human brains, Ménard says she and her team, including lead author Katarzyna Dudek, found the level of CB1 receptors on astrocytes in these parts of the brain was "lower in people with major depression at the time of death than in people without depression or those treated with antidepressants."

This validates the animal models, but more research is needed for a broader picture. The authors only measured one marker of inflammation in the brain, which does not fully reflect the complexity of the endocannabinoid system.

"Until we find a molecule that acts specifically on CB1 receptors in astrocytes, we can mitigate the negative repercussions of stress by taking advantage of the protective effect of physical activity," says Ménard.

The study was published in Nature Neuroscience.