Abstracts

Ionotropic and group I metabotropic glutamate (mGluR) receptor antagonists or group II/III mGluR agonists possess anticonvulsant properties. Recently, we sustained that subtype-selective targeting of glutamate receptors (e.g. with GLU[sub]K5[/sub] kainate antagonists) seems promising for future development of anticonvulsants for refractory psychomotor epilepsy with a minimum of adverse effects (Nat. Neurosci. 2002; 5(8):796-804). Moreover, depression is common among epileptic patients suffering from refractory seizures. The majority of data from animal models showed that decreases in serotonin (5-HT), dopamine (DA) and noradrenalin (NE) concentrations are involved in depression and do worsen seizures. We here investigated possible effects of several glutamate receptor ligands on the extracellular monoamines sampled with microdialysis from the hippocampus of conscious rats. Ligands were administered intrahippocampally via the microdialysis probe at anticonvulsant doses against pilocarpine-induced limbic seizures. Knowledge about hippocampal glutamate-monoamine interactions and about combined anticonvulsant-antidepressant properties of these molecules can have significant implications for the future drug treatment of depression in epileptic patients.
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. Following implantation of a microdialysis guide in dorsal hippocampus of male albino Wistar rats (270-300 g), a microdialysis probe (3 mm membrane) was inserted into the guide. Probes were continuously perfused overnight with modified Ringer[apos]s solution (2 [micro]l/min). The next day, 40 [micro]l dialysates were collected at 20 min time intervals from the conscious rats. After obtaining 6 baseline samples, an established anticonvulsant dose of a selective glutamate receptor ligand was administered for another 6 sampling periods. The monoamines in the dialysates were determined by microbore liquid chromatography with electrochemical detection.
Intrahippocampal perfusion of the selective AMPA receptor antagonist LY303070 (200 [micro]M), the GLU[sub]K5[/sub] kainate antagonist LY377770 (100 [micro]M) and the mGluR[sub]2/3[/sub] agonist LY379268 (100 [micro]M) did not alter extracellular monoamine levels in hippocampus. Similar experiments with the NMDA receptor antagonist MK801 (100 [micro]M) significantly increased hippocampal 5-HT, DA and NE release, while perfusion with the subtype-selective mGlu[sub]1a[/sub] antagonist LY367385 (1 mM) increased both hippocampal NE and DA concentrations but not 5-HT levels.
Extracellular hippocampal 5-HT, DA and NE levels are differently modulated by selective ionotropic and metabotropic glutamate receptor ligands at anticonvulsant doses. Increased hippocampal monoamine levels might be part of the anticonvulsant mechanism of action of both NMDA receptor antagonists and subtype-selective mGlu[sub]1a[/sub] antagonists.