title: Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy.
abstract: Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca(2+) current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.SWDs were immediately and substantially reduced (approximately 90%) by systemic administration of ETX (177-709 micromol/kg), or by bilateral microinfusion into the thalamus of the GABA(B) antagonist, CGP 36742 (5-27 nmol per side). However, infusion of ETX (1-200 nmol per side) into the ventrobasal complex or the NRT resulted in a reduction of SWDs that was delayed (30-60 min) and less marked (approximately 50%). Administration of ETX (0.2 mM to 1M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1mM. Only at 5mM were seizures significantly reduced (approximately 70%) within 30 min of administration. These results suggest that targeting of the thalamus alone may be insufficient for an immediate and full anti-absence action for ETX. Concomitant or exclusive actions in the cortex remain a possibility.
authors.affiliation: Department of Pharmacology, Division of Neuroscience, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. d.a.richards@bham.ac.uk
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Richards
authors.forename: Jon-Paul A
authors.initials: JP
authors.lastname: Manning
authors.forename: David
authors.initials: D
authors.lastname: Barnes
authors.forename: Laura
authors.initials: L
authors.lastname: Rombola
authors.forename: Norman G
authors.initials: NG
authors.lastname: Bowery
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Nathalie
authors.initials: N
authors.lastname: Leresche
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Crunelli
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004832:Epilepsy, Absence / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005013:Ethosuximide / Q000008:administration & dosage* / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013787:Thalamic Nuclei / Q000187:drug effects* / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D005013:Ethosuximide