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 act ion of diazepam in focally-evoked pilocarpine-induced seizures by concomita ntly assessing the changes produced in the extracellular levels of glutamat e, GABA (gamma-aminobutyric acid) and dopamine. In vivo microdialysis, coup led to continuous monitoring of electrocorticographic (ECoG) recordings, wa s performed in freely moving rats. Intrahippocampal perfusion with 10 mM pi locarpine (40 min, 2 mu l/min) produced limbic seizures. A single dose of i ntraperitoneal diazepam (5 mg/kg) was administered 2 h after pilocarpine pe rfusion was started. Dialysates were sampled both from hippocampus and cere bellum and analysed by microbore liquid chromatography. Diazepam produced i nstant inhibition of behavioural and ECoG seizure activity. Pilocarpine-ind uced increases in the extracellular levels of glutamate and dopamine in hip pocampus were promptly reduced by diazepam. No concurrent alterations in pi locarpine-induced increases in the extracellular levels of GABA in either h ippocampus or cerebellum were seen. Pilocarpine enhanced cerebellar glutama te levels only transiently and levels returned to baseline before diazepam administration. No further changes in cerebellar glutamate levels were obse rved 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 concurr ent alteration of pilocarpine-induced increases in endogenous GABA levels. Diazepam also significantly decreased pilocarpine-induced increases in extr acellular dopamine levels within the hippocampus. No immediate alterations of the basal levels of the neurotransmitters monitored were observed with d iazepam. (C) 1999 Elsevier Science B.V. All rights reserved.