Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors.
The present microdialysis study evaluated the anticonvulsant activity of extracellular hippocampal dopamine (DA) and serotonin (5-HT) with concomitant assessment of the possible mutual interactions between these monoamines. The anticonvulsant effects of intrahippocampally applied DA and 5-HT concentrations were evaluated against pilocarpine-induced seizures in conscious rats. DA or 5-HT perfusions protected the rats from limbic seizures as long as extracellular DA or 5-HT concentrations ranged, respectively, between 70-400% and 80-350% increases compared with the baseline levels. Co-perfusion with the selective D(2) blocker remoxipride or the selective 5-HT(1A) blocker WAY-100635 clearly abolished all anticonvulsant effects. These anticonvulsant effects were mediated independently since no mutual 5-HT and DA interactions were observed as long as extracellular DA and 5-HT levels remained within these protective ranges. Simultaneous D(2) and 5-HT(1A) receptor blockade significantly aggravated pilocarpine-induced seizures. High extracellular DA (> 1000% increases) or 5-HT (> 900% increases) concentrations also worsened seizure outcome. The latter proconvulsive effects were associated with significant increases in extracellular glutamate (Glu) and mutual increases in extracellular monoamines. Our results suggest that, within a certain concentration range, DA and 5-HT contribute independently to the prevention of hippocampal epileptogenesis via, respectively, D(2) and 5-HT(1A) receptor activation.
Clinckers
Ralph
R
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
Smolders
Ilse
I
Meurs
Alfred
A
Ebinger
Guy
G
Michotte
Yvette
Y
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology; D003292:Convulsants; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D014851:Wakefulness
D000927:Anticonvulsants; D003292:Convulsants; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D010862:Pilocarpine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D004298:Dopamine