Abstracts

Therapeutic concentrations of different anti-epileptic drugs increase extracellular levels of dopamine (DA) and /or serotonin (5-HT) in brain areas involved in epileptogenesis. On the other hand, seizure facilitation with monoaminergic and anti-epileptic drugs has often been associated with important increases in brain DA and 5-HT levels.
The present microdialysis study was aimed at investigating the effects of differently evoked hippocampal DA and 5-HT elevations against focal pilocarpine-induced limbic seizures in rats and to unravel the importance of both D[sub]2[/sub] and 5-HT[sub]1A[/sub] receptors in these effects.
Protocols were in accordance with National Rules on Animal Experiments and were approved by the Ethics Committee of the Faculty of Medicine [amp] Pharmacy, VUB. Twenty-four hours after stereotactic probe implantation in dorsal hippocampus, simultaneous microdialysis-electrocorticography experiments were performed on conscious male albino Wistars rats. Dialysates were collected every 20 min and analyzed for DA and 5-HT content via microbore LC. Pilocarpine was perfused through the probe (10 mM, 40 min) to evoke limbic seizures. During each collection period, seizure severity was assessed by scoring the typical behavioral changes. The total seizure severity score (TSSS) for each rat was obtained by summation of these SSS[rsquo]s.
Different concentrations of either DA (1-10 nM) and 5-HT (2-10 nM) were locally perfused and screened for anticonvulsant ability. Only a specific hippocampal extracellular concentration range protected the rats from seizures, whereas higher levels were shown not to be protective. Anticonvulsant threshold concentrations of the selective DA reuptake blocker GBR-12909 (100 [micro]M), the selective 5-HT reuptake blocker citalopram (1 [micro]M), oxcarbazepine (OXC) (100 [micro]M) and its active metabolite mono-hydroxy-carbamazepine (MHC) (250 [micro]M) evoked hippocampal DA and/or 5-HT increases within the protective ranges. Co-perfusion of these threshold concentrations with remoxipride (4 [micro]M), a selective D[sub]2[/sub] blocker, or WAY-100635 (100nM), a selective 5-HT[sub]1A[/sub] blocker cancelled all protective effects, despite the fact that DA and/or 5-HT levels remained within the protective ranges.
Increased DA-ergic and 5-HT-ergic hippocampal transmission, within a certain range, prevents the development of seizures via respectively D[sub]2[/sub] and 5-HT[sub]1A[/sub] receptor stimulation. These protective ranges facilitate the screening of different monoamine releasing agents in animal models for epilepsy, since drug doses can be adjusted according to their pharmacological effects on hippocampal DA and 5-HT.[figure1]