Valerian extract and valerenic acid are partial agonists of the 5-HT 5a receptor in vitro

Abstract

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian ( Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA A receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT 5a receptor, but only weak binding affinity to the 5-HT 2b and the serotonin transporter. Subsequent binding studies focused on the 5-HT 5a receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep–wake cycle. The PE extract inhibited [ 3H]lysergic acid diethylamide (LSD) binding to the human 5-HT 5a receptor (86% at 50 μg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC 50 curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC 50 of 15.7 ng/ml for the high-affinity state and 27.7 μg/ml for the low-affinity state. The addition of GTP (100 μM) resulted in a right-hand shift of the binding curve with an IC 50 of 11.4 μg/ml. Valerenic acid, the active constituent of both extracts, had an IC 50 of 17.2 μM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT 5a receptor.