Sensitivity of the circadian rhythm of kainic acid-induced convulsion susceptibility to manipulations of corticosterone levels and mineralocorticoid receptor binding.
Increases in corticosterone levels have been associated with enhanced susceptibility and decreases in corticosterone levels have been associated with decreased susceptibility to convulsions in mice. The proconvulsant effects of corticosterone are believed to be mediated by central mineralocorticoid receptors (MR). Both convulsion susceptibility and plasma corticosteroid levels display circadian rhythmicity. When corticosterone levels are at their lowest, hippocampal MR binding is submaximal, whereas when corticosterone levels are at their circadian peak, hippocampal MR binding is maximal. In the present experiments the relationship between circadian rhythms of susceptibility to kainic acid-induced convulsions and plasma corticosterone levels was investigated. In addition, the effects of exogenously administered corticosterone and the MR antagonist spironolactone were examined at times of different convulsion susceptibility. In general, lower plasma corticosterone levels were associated with decreased convulsion susceptibility and higher plasma corticosterone levels were associated with greater convulsion susceptibility. Corticosterone, administered when endogenous levels were low, had a proconvulsant effect. Spironolactone, administered when corticosterone levels were higher and hippocampal MR were presumably maximally occupied, had an anticonvulsant effect. These results indicate that the circadian rhythm in susceptibility to kainic acid-induced convulsions is sensitive to manipulations of corticosterone levels and MR binding. Degree of central MR occupancy may, in part, mediate convulsion susceptibility in humans as well as laboratory animals.
Department of Medical Psychology, Oregon Health Sciences University, Portland.
A J
AJ
Roberts
L D
LD
Keith
D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D003345:Corticosterone / Q000097:blood* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D007608:Kainic Acid; D003345:Corticosterone