Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats.
In order to investigate the mechanism of action of anticonvulsant drugs, we examined the effects of carbamazepine (CBZ) and antiepilepsirine (AE) on convulsions and on brain biogenic amines in genetically epilepsy-prone rats (GEPR). AE was an effective anticonvulsant in moderate seizure GEPR (GEPR-3, ED50 = 65.5 mg/kg) and in severe seizure GEPR (GEPR-9, ED50 = 68.5 mg/kg). Because GEPR are known to have deficiencies in brain norepinephrine (NE) and serotonin (5-HT), which are of etiologic significance in their seizure predisposition, we evaluated the effects of anticonvulsant doses of CBZ and AE on dialyzable NE, 5-HT and their metabolites. Dialysis probes were stereotaxically inserted into hippocampi of awake and unrestrained GEPR-3 and GEPR-9. Either AE (100 mg/kg in GEPR-3; 100 mg/kg in GEPR-9) or CBZ (45 mg/kg in GEPR-3; 6 mg/kg in GEPR-9) was administered i.p. after establishing basal release. Significant increases in dialyzable 5-HT, but not NE, were seen at the approximate time to peak anticonvulsant effect for each drug in both strains. The changes in 5-HT release remained closely associated with the anticonvulsant actions after i.v. administration of either AE (40 mg/kg) or CBZ (25 mg/kg) in GEPR-3. Pretreatment of GEPR-9 with p-chlorophenylalanine depleted brain 5-HT and greatly diminished the anticonvulsant effectiveness of both drugs. We conclude that both CBZ and AE are effective anticonvulsants in GEPR and that enhancement of serotonergic transmission may contribute to the anticonvulsant effect of these drugs.
Yan
Q S
QS
Department of Basic Sciences University of Illinois College of Medicine, Peoria.
Mishra
P K
PK
Burger
R L
RL
Bettendorf
A F
AF
Jobe
P C
PC
Dailey
J W
JW
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*
D000927:Anticonvulsants; D010880:Piperidines; D012701:Serotonin; D002220:Carbamazepine; D006897:Hydroxyindoleacetic Acid; C037547:ilepcimide