Anticonvulsant action of GBR-12909 and citalopram against acute experimentally induced limbic seizures.
We recently showed that intrahippocampally administered dopamine and serotonin exert concentration-dependent non-protective, protective and proconvulsant effects against limbic seizures in rats. Anticonvulsant action was mediated via, respectively, hippocampal D2 and 5-HT1A receptor stimulation, while proconvulsant effects were associated with concomitant hippocampal glutamate increases. We here examined whether increases in endogenous hippocampal dopamine and serotonin exert similar actions. Initially, dose-response experiments were performed with intrahippocampal perfusions of GBR-12909 and citalopram, respectively, selective dopamine and serotonin re-uptake blockers. Based on their effects on monoaminergic release, a potential non-protective, protective and proconvulsant concentration was selected. The predicted non-protective GBR-12909 (10 microM) and citalopram (0.5 microM) concentrations failed to prevent pilocarpine-induced seizures. The predicted protective GBR-12909 (100 microM) and citalopram (1 microM) perfusions resulted in complete anticonvulsant action, again mediated by D2 and 5-HT1A receptors. Unexpectedly, at predicted proconvulsant concentrations complete anticonvulsant action was obtained and hippocampal Glu remained unaltered. This study shows that selective monoamine re-uptake blockers have important anticonvulsant properties. Based on the previously established anticonvulsant monoamine ranges, anticonvulsant threshold concentrations can be predicted for compounds with endogenous dopamine or serotonin promoting effects. Non-selective actions curtailing glutamatergic activity may further be responsible for the unexpected anticonvulsant effects at predicted proconvulsant concentrations.
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
D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants; D015306:Biogenic Monoamines / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008032:Limbic System / Q000503:physiopathology*; D008297:Male; D017551:Microdialysis; D018721:Muscarinic Agonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017330:Remoxipride / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000927:Anticonvulsants; D015306:Biogenic Monoamines; D015283:Citalopram; D004298:Dopamine; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018721:Muscarinic Agonists; D010862:Pilocarpine; D010879:Piperazines; D011725:Pyridines; D017330:Remoxipride; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C043425:vanoxerine