The brain is rich with cannabinoid receptor type 1 (CB1R), they are what THC binds to give the psychoactive effects of cannabis. Their roles are complex and sometimes counter-intuitive. The authors of this research looked at how a CB1R agonist (that is, a cannabinoid that binds to CB1R) could both cause anxious feelings and relieve them. This dual effect is called a biphasic effect and is very important in many processes in the body.
At low concentrations, the cannabinoid CP-55940 activated CB1R in cortical glutamatergic terminals (certain specific neuronal connections), inducing an anxiolytic effect in rodents.
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At higher concentrations, CP-55940 induced anxiety-like effects on GABAergic terminals, which are in a different part of the brain. This research reveals a lot about how the brain regulates emotions and shows potential pathways for anxiolytic cannabinoid drug development.
To reveal how CB1R is used in the brain in anxiogenesis and anxiolysis, CB1R was knocked out, or disabled, in two different areas of the brain in two different mice populations.
These areas were chosen because they had been previously shown to be activated in anxiety. In one, CB1R was deleted in GABAergic neurons in the forebrain. In the other population, CB1R was deleted from cortical glutamatergic neurons.
Both populations were then administered low and high doses of the cannabinoid CP-55940, which binds to CB1R and can generate anxiolytic and anxiogenic effects. In the absence of forebrain CB1R, low doses relieved and high doses did not have the anxiogenic effects.
When cortical CB1R were knocked out, a low dose of CP-55940 did not relieve anxiety and a high dose induced anxiety. This biphasic effect shows clearly that low and high doses have different effects on CB1R in different parts of the brain that regulate anxiety.
Clearly, the brains of mammals have evolved to use biphasic endocannabinoid effects very effectively. Differing effects from different concentrations in different parts of the brain add a level of regulation and adaptiveness to a system that has been useful evolutionary.
In terms of understanding the brain, this knowledge of biphasic interactions adds substantially to our model of how the brain mediates emotional regulation. For therapy, the findings are very important. Knowing how to administer a drug is as important as knowing which drug to take.
By targeting the endocannabinoid system in a more precise manner, drugs and methods of delivery can be developed that can have much safer and more effective anxiolytic effects. Now that the mechanism for anxiety regulation is at least partly understood, it can be interacted with in an informed manner.
The GABA and glutamatergic systems talk to each other in a way that is mediated with cannabinoids. This crosstalk needs cannabinoids to maintain a balance, and it is hypothesized that a dysregulation of this balance can result in anxiety or anxiety disorders. It is therefore a very hopeful target for precise cannabinoid anxiety therapy.
This study showed, through knocking out cannabinoid receptors in different parts of the brain that are involved in anxiety, that GABA and glutamate signaling are engaged in an interactive crosstalk that needs cannabinoid receptors to help regulate it.