The GABA(A) receptor mediates the hypnotic activity of melatonin in rats.

The present investigation assessed whether hypnotic activity of melatonin was mediated by the GABA(A) receptor in rats. Electroencephalography (EEG) was measured in this experiment. Melatonin, at a dose of 10 mg/kg ip, showed a significant sleep-promoting effect in rats. Flumazenil (3.5 and 7 mg/kg), a specific antagonist of the benzodiazepine (BZP) recognition site on the GABA(A) receptor, and picrotoxin (2 and 4 mg/kg), the ligand of the picrotoxin site on the GABA(A) receptor, seemed to be devoid of intrinsic influence on each sleep parameter when used alone, but they significantly antagonized the melatonin-induced increase in total sleep time (TS), slow-wave sleep time (SWS) and paradoxical sleep time (PS), and the decrease in time to sleep onset (TSO) and wakefulness time (W). A significant interaction was shown between melatonin and flumazenil or picrotoxin. When bicuculline methiodide (2 and 4 mg/kg), a specific antagonist of the GABA binding site on the GABA(A) receptor, was used together with melatonin, the melatonin-induced increase in TS, SWS and PS, and the decrease in W were abolished. However, there was no interaction between melatonin and bicuculline methiodide on sleep parameters except PS. These results indicate that the hypnotic activity of melatonin may be linked to the GABA(A) receptor and mediated through the BZP recognition site, the picrotoxin site on the GABA(A) receptor and partially through the GABA binding site on the GABA(A) receptor.