We come close to understanding how drugs function. In reality, though, scientists face an enormous challenge in mapping the body. Binding sites that accept cannabis ingredients, for example, can sometimes form complexes with other receptors, merging their two separate sets of effects. A new discovery connects the cannabinoid 1 receptor with a different receptor that, in part, controls dopamine during Parkinson’s Disease. The complex occurs between CB1 receptors and the angiotensin receptor — AT2.
What is angiotensin?
The renin-angiotensin system (RAS) regulates blood pressure, to name just its primary purpose. Essentially, low blood pressure signals the release of renin, which is a special type of biological machine known as an enzyme. That enzyme causes a reaction in your body’s blood vessels (angio) that causes constriction (tensin). The messenger molecule known as angiotensin II targets one primary receptor, AT1, but also binds to two lesser regulatory receptors.
It turns out that we have to add a whole new list of effects to our favorite cannabinoids — depending on each individual’s current health status. A recent study published in the journal of Experimental Neurology focused on AT2, a receptor expressed during fetal life that almost vanishes in its entirety after a person comes into the world. Yet, the minor RAS receptor bounces back in adulthood during injury. And when AT2 does reappear, it might form a complex with the endocannabinoid system, therefore, responding to THC and other cannabinoids.
The heart, brain, and adrenal glands express AT2, whose primary purpose is to control overactive angiotensin one. Yet the two AT receptors are only around 34% similar. In fact, minus a few additional connections to dopamine, AT2 facilitates many of the same non-psychotropic effects that THC causes through the CB1 receptor. The latest discovery focused on the newly found complex in neurons situated in the center of the brain. While researchers extracted neurons from the basal ganglia region of mouse embryos. They also tested living rats with a drug-induced motor deficit. The paper concluded that the cannabinoid 1 receptor, through AT2, interacts with a dopamine precursor during Parkinson’s Disease.
Cannabis and Parkinson’s, with and without Dyskinesia
A person loses critical dopamine receptors while Parkinson’s Disease progresses, which impedes vital motor control. Drugs that activate the Renin-Angiotensin System (RAS) assist patients with specific neurodegenerative diseases. But the fact that a toxic CB1 blocker, Rimonabant, simultaneously inhibits the AT2 receptor was a ten-year-old mystery. The interaction, known as cross-antagonism, meant that CB1 receptor agonists should help improve motor function in patients with dopamine neuron degradation, in theory. Interestingly, AT2 inhibitors do not affect cannabinoid receptors. And until now, scientists failed to map connections between the two receptors.
A team of researchers from Spain authored the new study on novel AT2-CB1 complexes in Parkinson’s Disease. They also confirmed that the heteromers occur in Human Embryonic Kidney cells. To further confirm their results, researchers gave rats with defective dopamine neurons an amino acid that makes dopamine and adrenaline known as L-DOPA. For reasons still unknown to science, L-DOPA causes Dyskinesia as a side effect in certain individuals (humans or rodents), which appears as unorthodox muscle spasms. The Spanish researchers found out that L-DOPA reduced the cannabinoid-angiotensin receptor complex, except in rodents experiencing Dyskinesia symptoms.
Roots growing in endocannabinology
Cells and receptors can bit lit up with fluorescent proteins, such as luciferase. Scans taken with special imaging techniques reveal those glowing cells, which can help identify two receptors coexpressing in one cell. The study authors used a similar method for identifying AT2-CB1 receptor heteromers, but images do not reveal their interaction. Results from the in vitro test confirmed discoveries made in living rats. In a test tube experiment, they tested each isolated receptor in a cellular assay and compared their results to AT2-CB1 receptor pairs. (1)
The researchers suggested, "any therapeutic development focused on the CB1r should consider that the cannabinoid receptor can interact in basal ganglia neurons with the AT2R, whose activation correlates with the stimulation of mechanisms that prevent addictive behaviors  and possibly neurodegenerative/neuroinflammatory diseases."
Discoveries that conclude biological outcomes can sometimes solve mysteries. But in the case of CB1 receptors and their ability to potentially treat Parkinson’s Disease through an indirect effect on dopamine, there are simply more synergies left to explore. At the same time, researchers in more and more fields find themselves dependent on endocannabinology.
Rivas-Santisteban, R., Lillo, J., Raïch, I., Muñoz, A., Lillo, A., Rodríguez-Pérez, A. I., Labandeira-García, J. L., Navarro, G., & Franco, R. (2023). The cannabinoid CB1 receptor interacts with the angiotensin AT2 receptor. Overexpression of AT2-CB1 receptor heteromers in the striatum of 6-hydroxydopamine hemilesioned rats. Experimental neurology, 362, 114319.
Nakaoka, H., Mogi, M., Kan-No, H., Tsukuda, K., Ohshima, K., Wang, X.L., Chisaka, T., Bai, H.Y., Shan, B.S., Kukida, M., Iwanami, J., Horiuchi, M., 2015. Angiotensin II type 2 receptor signaling affects dopamine levels in the brain and prevents binge eating disorder. J. Renin-Angiotensin-Aldosterone Syst. 16, 749–757.