Effects of diazepam on extracellular brain neurotransmitters in pilocarpine-induced seizures in rats.
The present study was undertaken to gain insights into the mechanism of action of diazepam in focally-evoked pilocarpine-induced seizures by concomitantly assessing the changes produced in the extracellular levels of glutamate, GABA (gamma-aminobutyric acid) and dopamine. In vivo microdialysis, coupled to continuous monitoring of electrocorticographic (ECoG) recordings, was performed in freely moving rats. Intrahippocampal perfusion with 10 mM pilocarpine (40 min, 2 microl/min) produced limbic seizures. A single dose of intraperitoneal diazepam (5 mg/kg) was administered 2 h after pilocarpine perfusion was started. Dialysates were sampled both from hippocampus and cerebellum and analysed by microbore liquid chromatography. Diazepam produced instant inhibition of behavioural and ECoG seizure activity. Pilocarpine-induced increases in the extracellular levels of glutamate and dopamine in hippocampus were promptly reduced by diazepam. No concurrent alterations in pilocarpine-induced increases in the extracellular levels of GABA in either hippocampus or cerebellum were seen. Pilocarpine enhanced cerebellar glutamate levels only transiently and levels returned to baseline before diazepam administration. No further changes in cerebellar glutamate levels were observed with diazepam. Our findings suggest that the anti-convulsant action of diazepam against pilocarpine-induced seizures is associated with a prompt attenuation of extracellular hippocampal glutamate overflow without concurrent alteration of pilocarpine-induced increases in endogenous GABA levels. Diazepam also significantly decreased pilocarpine-induced increases in extracellular dopamine levels within the hippocampus. No immediate alterations of the basal levels of the neurotransmitters monitored were observed with diazepam.
Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussels, Belgium.
G M
GM
Khan
I
I
Smolders
H
H
Lindekens
J
J
Manil
G
G
Ebinger
Y
Y
Michotte
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018757:GABA Modulators / Q000494:pharmacology*; D005971:Glutamates / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010862:Pilocarpine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D018757:GABA Modulators; D005971:Glutamates; D018377:Neurotransmitter Agents; D010862:Pilocarpine; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D004298:Dopamine