Cannabidiol Acts at 5-HT(1A) Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

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 (n = 11) and from a group of autopsies (n = 11). The [(3)H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT(1A) receptors. The [(35)S]-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 (pK(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 [(35)S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (p > 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%, p < 0.0001; temporal neocortex, 71.5%, p < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, p < 0.0001; temporal neocortex, 68.5%, p < 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.