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

Abstract

Experimental evidence indicates that cannabidiol (CBD) induces anxiolytic and antiepileptic effects through the activation of 5-HT_1A receptors. These receptors are coupled to G_i/o proteins and induce inhibitory effects. At present, the interaction of CBD with 5-HT_1A receptors in the human brain is unknown. The aim of this study focused on evaluating the interaction between CBD and 5-HT_1A receptors in cell membranes obtained from the hippocampus and temporal neocortex of autopsies and patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). Cell membranes were isolated from the hippocampus and temporal neocortex of a group of patients with DR-MTLE who were submitted to epilepsy surgery (<i>n</i> = 11) and from a group of autopsies (<i>n</i> = 11). The [³H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT_1A receptors. The [³⁵S]-GTPγS assay was used to investigate the CBD-induced activation of G_i/o proteins through its action on 5-HT_1A receptors.The CBD affinity (p<i>K</i> _i) for 5-HT_1A receptors was similar for autopsies and patients with DR-MTLE (hippocampus: 4.29 and 4.47, respectively; temporal neocortex: 4.67 and 4.74, respectively). Concerning the [³⁵S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (<i>p</i> > 0.05) at low CBD concentrations (1 pM to 10 μM). In contrast, at high concentrations (100 μM), CBD reduced the constitutive activity of G_i/o proteins of autopsies and DR-MTLE patients (hippocampus: 39.2% and 39.6%, respectively; temporal neocortex: 35.2% and 24.4%, respectively). These changes were partially reversed in the presence of WAY-100635, an antagonist of 5-HT_1A receptors, in the autopsy group (hippocampus, 59.8%, <i>p</i> < 0.0001; temporal neocortex, 71.5%, <i>p</i> < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, <i>p</i> < 0.0001; temporal neocortex, 68.5%, <i>p</i> < 0.001). Our results show that CBD interacts with human 5-HT_1A receptors of the hippocampus and temporal neocortex. At low concentrations, the effect of CBD upon G_i/o protein activation is limited. However, at high concentrations, CBD acts as an inverse agonist of 5-HT_1A receptors. This effect could modify neuronal excitation and epileptic seizures in patients with DR-MTLE.