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

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 D 2 and 5-HT 1A 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 μM) and citalopram (0.5 μM) concentrations failed to prevent pilocarpine-induced seizures. The predicted protective GBR-12909 (100 μM) and citalopram (1 μM) perfusions resulted in complete anticonvulsant action, again mediated by D 2 and 5-HT 1A 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.