Hippocampal melatonin receptors modulate seizure threshold.
OBJECTIVE
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 Mel(1b) 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 Mel(1a)/Mel(1b) receptor antagonist luzindole also increased seizure latency but to a lesser degree than 4-P-PDOT. The behavioral effects of Mel(1b) receptor inhibition were comparable to those of the gamma-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 GABA(A) antagonist bicuculline.


CONCLUSIONS
Our results suggest that nocturnal activation of hippocampal Mel(1b) receptors depresses GABA(A) receptor function in the hippocampus and enhances seizure susceptibility.
Stewart
Lee S
LS
Program in Neuroscience, Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada. lee.stewart@mcgill.ca
Leung
L Stan
LS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects / Q000706:statistics & numerical data; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
C114459:4-phenyl-2-propionamidotetraline; D018756:GABA Antagonists; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; D010862:Pilocarpine; C057154:luzindole; D009118:Muscimol