3-Carene, a Phytoncide from Pine Tree Has a Sleep-enhancing Effect by Targeting the GABAA-benzodiazepine Receptors.

3-Carene, a bicyclic monoterpene, is one of the major components of the pine tree essential oils. It has been reported that, in addition to its known properties as a phytoncide, 3-carene has anti-inflammatory, antimicrobial, and anxiolytic effects. We have previously demonstrated that α-pinene, the major component of pine tree, has a hypnotic effect through GABA_A-benzodiazepine (BZD) receptors. However, a hypnotic effect of 3-carene has not been studied yet. Here, we report that oral administration of 3-carene increases the sleep duration and reduces sleep latency in pentobarbital- induced sleep test. 3-Carene potentiates the GABA_A receptor-mediated synaptic responses by prolonging the decay time constant of inhibitory synaptic responses. These enhancing effects of 3-carene are reproduced by zolpidem, a modulator for GABA_A-BZD receptor, and fully inhibited by flumazenil, an antagonist for GABA_A-BZD receptor. The molecular docking of 3-carene to the BZD site of GABA_A protein structure, suggests that 3-carene binds to the BZD site of α1 and ϒ2 subunits of GABA_A-BZD receptor. These results indicate that, similar to α-pinene, 3-carene shows a sleep-enhancing effect by acting as a positive modulator for GABA_A-BZD receptor.