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Neuropharmacology. 2004 Dec;47(7):1053-61.

Anticonvulsant action of GBR-12909 and citalopram against acute experimentally induced limbic seizures.

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1
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.

Abstract

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.

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