Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

• Published in: Epilepsy research 2003-05, Vol.54 (2), p.97-107
• Main Authors: Richards, Douglas A, Manning, Jon-Paul A, Barnes, David, Rombola, Laura, Bowery, Norman G, Caccia, Silvio, Leresche, Nathalie, Crunelli, Vincenzo
• Format: Article
• Language: English
• Subjects: Absence epilepsy; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - blood; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Cognitive Sciences; Disease Models, Animal; Drug Delivery Systems - methods; Epilepsy, Absence - blood; Epilepsy, Absence - drug therapy; Epilepsy, Absence - physiopathology; Ethosuximide; Ethosuximide - administration & dosage; Ethosuximide - blood; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Life Sciences; Medical sciences; Microdialysis; Nervous system (semeiology, syndromes); Neurology; Neurons and Cognition; Neuropharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Reticular thalamic nucleus; Spike–wave discharge; Thalamic Nuclei - drug effects; Thalamic Nuclei - physiology; Ventrobasal thalamic complex
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/S0920-1211(03)00060-3

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 (∼90%) by systemic administration of ETX (177–709 μmol/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 (∼50%). Administration of ETX (0.2 mM to 1 M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1 mM. Only at 5 mM were seizures significantly reduced (∼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.