Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

Epilepsy is a very common disorder characterized by recurrent, spontaneous seizures, and a seizure is induced by the abnormal, synchronous excitation of neurons in the brain. Gi/o proteins inside neurons, when activated, can trigger a sequence of biomolecular events that ultimately results in decreased excitability of neurons, thereby lessening the likelihood of seizure. One of the receptors that can activate neuronal Gi/o proteins is 5-HT1A, a lesser known and studied target of cannabidiol (CBD), a major component of the plant cannabis.

More specifically, CBD has recently been shown to bind to 5-HT1A receptors with significant affinity in two structures, the hippocampus and the temporal cortex, of brain slices obtained from both autopsies of people without epilepsy and surgeries of epilepsy patients. At a low concentration, CBD doesn’t induce changes to the function of Gi/o proteins; however, at a high concentration, it reverses the effect of 5-HT1A , reducing the constitutive activity of Gi/o proteins. Such effects classify CBD as an “inverse agonist” of 5-HT1A – a compound that interacts with but induces downstream processes opposite to the receptor’s original effects.

In light of this finding, that antiepileptic is one of the most thoroughly proven medical benefits of CBD seems counterintuitive: Wouldn’t CBD, through inhibiting the activity of Gi/o proteins, heighten neuronal excitability and susceptibility to seizure? As an explanation, scientists cite evidence that inverse agonists, after reversing the effects of their targeted receptors, prompt the brain to increase the expression of those receptors on cell surface, thereby indirectly increasing the signalling of said receptors. Because of this mechanism, scientists hypothesize that continuous administration of CBD, an inverse agonist of 5-HT1A receptor, can enhance the abundance of this receptor, augment Gi/o protein functions, and ultimately protect the brain from epilepsy.


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