Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine.
We recently showed that dopamine (DA) and serotonin (5-HT) exert anticonvulsant effects against limbic seizures in rats mediated by hippocampal D(2) and 5-HT(1A) receptor stimulation. For exogenously administered monoamines, anticonvulsant activity was only observed following 70--400% and 80--350% increases in baseline levels for dopamine and serotonin, respectively. The aim of the present microdialysis study was to investigate whether oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxycarbamazepine (MHD) promote the release of hippocampal monoamines. Initially, concentration-response experiments were performed. Different concentrations of both compounds were perfused into the hippocampus via the microdialysis probe and tested for their effects on extracellular monoamine levels and anticonvulsant properties against pilocarpine-evoked seizures in rats. Anticonvulsant activity was always accompanied by significant increases in dopamine and serotonin levels. The anticonvulsant threshold concentrations for oxcarbazepine (100 microM) and 10,11-dihydro-10-hydroxycarbamazepine (250 microM) were associated with, respectively, 140 and 205% increases in hippocampal dopamine and 288 and 176% increases in serotonin concentrations. Co-perfusion of these anticonvulsant threshold concentrations for both compounds either with a selective D(2) or 5-HT(1A) antagonist abolished all anticonvulsant effects. This study shows that oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine exert important monoamine promoting effects that, at least partly, contribute to the anticonvulsant mechanism of action of these compounds. The effects on dopamine and serotonin levels are therefore proposed as pharmacodynamic markers for the anticonvulsant activity of these compounds. These pharmacodynamic markers are here shown to be useful for the selection of anticonvulsant threshold concentrations of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine.
Clinckers
Ralph
R
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Smolders
Ilse
I
Meurs
Alfred
A
Ebinger
Guy
G
Michotte
Yvette
Y
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D016896:Treatment Outcome
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D015415:Biomarkers; C476610:oxcarbamazepine; D012701:Serotonin; D002220:Carbamazepine; D004298:Dopamine