title: In vivo modulatory action of extracellular glutamate on the anticonvulsant effects of hippocampal dopamine and serotonin.
abstract: OBJECTIVE
  Our recent work (Clinckers et al., J Neurochem 2004;89:834-43) demonstrated that intrahippocampal perfusion of 2 nM dopamine or serotonin via a microdialysis probe offered complete protection against focal pilocarpine-induced limbic seizures and did not influence basal extracellular hippocampal glutamate levels. Ten nanomolar dopamine or serotonin perfusion, however, worsened seizures and was accompanied by significant extracellular glutamate increases to approximately 200%. The significance of these glutamate elevations in seizure generation remains unclear. The present microdialysis study investigated the modulatory role of extracellular hippocampal glutamate levels in these monoaminergic protective and proconvulsant effects.
  
  
  METHODS
  A first group of male Wistar albino rats was perfused intrahippocampally for 240 min with 6.25 microM glutamate alone to increase extracellular levels by 200%. Other animals were perfused with anticonvulsant concentrations of monoamines throughout the experiments while receiving continuous coperfusions of 6.25 microM glutamate either before, during, and after (240 min) or only after (100 min) pilocarpine perfusion (40 min). Rats were scored for epileptic behavior, and the mean scores were compared with those of the control group. Microdialysates were analyzed for monoamine and glutamate content with microbore liquid chromatography.
  
  
  RESULTS
  No convulsions occurred during glutamate perfusion alone. When monoamines and glutamate were coperfused before pilocarpine administration, the anticonvulsant effect of the monoamines was lost. Glutamate addition after pilocarpine administration did not affect monoaminergic seizure protection.
  
  
  CONCLUSIONS
  These results indicate that extracellular glutamate increases per se do not necessarily induce seizures but that they can modulate the anticonvulsant effects exerted by hippocampal monoamines.
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ralph
authors.initials: R
authors.lastname: Clinckers
authors.forename: Sarah
authors.initials: S
authors.lastname: Gheuens
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Alfred
authors.initials: A
authors.lastname: Meurs
authors.forename: Guy
authors.initials: G
authors.lastname: Ebinger
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D008032:Limbic System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D010862:Pilocarpine; D012701:Serotonin; D018698:Glutamic Acid; D004298:Dopamine