Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

γ-Aminobutyric acid type A receptors (GABA(A)Rs) are the main inhibitory mediators in the central nervous system (CNS). GABA(A)Rs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABA(A)Rs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABA(A)Rs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABA(A)Rs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABA(A)Rs.