Abstract

The pineal hormone, melatonin, can exert sedative/hypnotic, anxiolytic and other neuropharmacological effects in experimental animals. Usually, these effects are produced by large pharmacological doses of melatonin, which are known to interact with benzodiazepine (BZ) receptors in the central nervous system (CNS). There is evidence that flumazenil, a specific central-type BZ antagonist, can block some of these effects of melatonin. Therefore, it is thought that activation of central-type BZ receptors on the BZ-GABA A receptor complex, with consequent allosteric enhancement of GABAergic activity, is the primary mechanism underlying the neuropharmacological effects of melatonin. In addition, melatonin can interact with other BZ receptor subtypes to influence neurosteroidogenesis and cyclic AMP production, which can further modulate GABAergic activity in the CNS. However, in contrast to the high pharmacological doses of melatonin used in animal studies, the relatively low doses of this hormone, typically used in human sleep studies, are unlikely to reach the micromolar threshold required for binding to BZ receptors. In support of this view, flumazenil does not block the sedative/hypnotic effect observed in young adults following administration of a low pharmacological dose of 3 mg melatonin. Thus, while pharmacological sedation by high doses of melatonin is thought to involve enhancement of BZ-GABA A receptor signaling, it appears that physiological receptors and mechanisms mediate sleep induction by low doses of this psychotropic hormone in humans.