Scutellaria lateriflora (American Skullcap) is a wetland plant of the mint (Lamiaceae) family, native to North America, with an indigenous history of use as a sedative and anxiolytic. Given its demonstrated behavioral properties, we sought to clarify the molecular pharmacodynamics of American Skullcap; specifically, we ask if extracts of S. lateriflora are able to directly activate and/or allosterically potentiate gamma-aminobutyric acid type A (GABA(A)) receptors. The GABA(A) receptor is the primary inhibitory neurotransmitter receptor in the central nervous system of vertebrates and is a canonical target of anxiolytic and sedating compounds, such as benzodiazepines, barbiturates, endogenous neurosteroids, and general anesthetics. Using two-electrode voltage clamping, we show that S. lateriflora directly activates both α;1ß2 γ ;2 and α;1ß2 GABA(A) receptors heterologously expressed in Xenopus laevis oocytes. Co-application of gabazine, an orthosteric antagonist, with S. lateriflora extract only partially attenuated its ability to directly activate the receptor, suggesting that the GABA-mimetic abilities of the extract are not occurring at the orthosteric binding site. Moreover, co-application with flumazenil, a benzodiazepine-site antagonist, did not significantly alter S. lateriflora direct activation. Taken together, these observations are consistent with the hypothesis that S. lateriflora acts elsewhere on the receptor to directly gate the channel. Our research suggests an important role for the GABA(A) receptor in mediating the anxiolytic and sedating actions of American Skullcap. Our results have the potential to aid in the development of novel pharmacotherapies for anxiety and insomnia.
Brown et al. (Sun,) studied this question.