Substantia nigra is an anticonvulsant site of action of topiramate in the focal pilocarpine model of limbic seizures.
OBJECTIVE
The substantia nigra pars reticulata (SNR) is known to play a role in gating and control of seizures. Prompted by the observation that intrahippocampal topiramate (TPM) administration does not suppress limbic seizures in the focal pilocarpine model, we investigated the role of the SNR in the anticonvulsant mechanism of action of TPM.


METHODS
Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. Changes in hippocampal extracellular (EC) glutamate and GABA concentrations were monitored. Effects of intraperitoneal (10-200 mg/kg), intrahippocampal (1-5 mM), and bilateral intranigral (100-300 nmol) TPM administration on pilocarpine-induced seizures and neurochemical changes were evaluated. Effects of TPM administration alone on hippocampal and nigral EC amino acid concentrations were also studied.


RESULTS
Systemic and intranigral, but not intrahippocampal TPM administration suppressed pilocarpine-induced seizures and neurochemical changes. Nigral GABA(A) receptor blockade by picrotoxin abolished the anticonvulsant effect of TPM in SNR. Systemic TPM administration increased hippocampal glutamate and decreased GABA. Intranigral TPM administration increased hippocampal glutamate, but not GABA. Intrahippocampal TPM increased hippocampal glutamate and GABA, but only at high concentrations.


CONCLUSIONS
In the focal pilocarpine model, TPM does not exert its anticonvulsant effect at the site of seizure initiation. We identified the SNR as a site of action of TPM, and showed that the nigral GABA-ergic system is central to TPM's anticonvulsant effect in SNR. Anticonvulsant effects and neurochemical changes in hippocampus following intranigral TPM administration suggest the existence of a nigro-hippocampal circuit, which may be involved in the control of limbic seizures.
Meurs
Alfred
A
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
Clinckers
Ralph
R
Ebinger
Guy
G
Michotte
Yvette
Y
Smolders
Ilse
I
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D005971:Glutamates / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*; D013378:Substantia Nigra / Q000187:drug effects* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D005971:Glutamates; D010862:Pilocarpine; D000077236:Topiramate; D005632:Fructose; D005680:gamma-Aminobutyric Acid