Hippocampal melatonin receptors modulate seizure threshold

Abstract

Purpose: The pineal hormone melatonin has been shown to enhance hippocampal excitability. We therefore investigated whether inactivation of hippocampal melatonin receptors affects behavioral seizures. Methods: Intrahippocampal infusions were performed in rats to study the effect of different melatonin receptor antagonists on behavioral activity, EEG, and seizure susceptibility. Experiments were conducted at 2 times of the day that coincided with the peak and trough of the daily melatonin rhythm. Results: Local infusion of the Mel1b receptor antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT) into the hippocampus, but not the overlying neocortex, significantly increased seizure latency and in some cases provided complete protection against seizure development. In addition, 4-P-PDOT suppressed open field activity and hippocampal EEG amplitude. The mixed Mel1a/Mel1b receptor antagonist luzindole also increased seizure latency but to a lesser degree than 4-P-PDOT. The behavioral effects of Mel1b receptor inhibition were comparable to those of the γ-aminobutyric acid (GABA)A receptor agonist muscimol and were observed during the dark phase (2400-0200 h) but not the light phase (1200-1400 h) of the daily photocycle. The anticonvulsant effect of intrahippocampal infusion of 4P-P-DOT was blocked by coadministration of the GABAA antagonist bicuculline. Conclusions: Our results suggest that nocturnal activation of hippocampal Mel1b receptors depresses GABAA receptor function in the hippocampus and enhances seizure susceptibility. © 2005 International League Against Epilepsy.