Actions of U-92032, a T-type Ca2+ channel antagonist, support a functional linkage between I(T) and slow intrathalamic rhythms.

Abstract

Thalamic relay neurons express high levels of T-type Ca(2+) channels, which support the generation of robust burst discharges. This intrinsically mediated form of phasic spike firing is thought to be critical in the generation of slow (3-4 Hz) synchronous oscillatory activity of absence epilepsy. Recordings made from brain slices or whole animals have shown that slow synchronous absence-like activity can be abolished when Ca(2+)-dependent burst firing in relay neurons is interrupted by the pharmacological or genetic inactivation of T-channels. Because succinimide drugs act as incomplete and nonspecific antagonists, we tested whether the novel T-channel antagonist U-92032 could provide stronger support for a role of T-channels in slow oscillatory activity. Ca(2+)-dependent rebound (LTS) bursts were recorded using whole cell current clamp in relay cells of the ventral basal complex (VB) from thalamic slices of adult rats. We used LTS kinetics to measure the availability of T-channels in VB cells after TTX. U-92032 (1 and 10 microM) reduced the maximum rate of depolarization of the isolated LTS by 51% and 90%, respectively, compared with the 35% reduction due to 2 mM methylphenylsuccinimide (MPS), the active metabolite of the antiabsence drug methsuximide. U-92032 (1 and 10 microM) also suppressed evoked, slow oscillations in thalamic slices with a time course similar for observed intracellular effects. Unlike MPS, we observed no substantial effects of short-term U-92032 applications (< or =2 h) on the generation of action potentials in VB cells. Our findings show U-92032 is a more potent, effective, and specific T-channel antagonist than previously studied succinimide antiabsence drugs and that it dramatically reduces epileptiform synchronous activity. This suggests that U-92032 or other specific T-channel antagonists may provide effective drug treatments for absence epilepsy.

• Authors: Darrell M Porcello, Stephen D Smith, John R Huguenard
• Journal: Journal of neurophysiology (J Neurophysiol) Vol. 89 Issue 1 Pg. 177-85 (Jan 2003) ISSN: 0022-3077 [Print] United States
• PMID: 12522170 (Publication Type: Journal Article)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, T-Type
• Piperazines
• Succinimides
• methsuximide
• U 92032
• Tropolone

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, T-Type (metabolism)
• Epilepsy, Absence (drug therapy, physiopathology)
• Female
• Male
• Neurons (physiology)
• Organ Culture Techniques
• Periodicity
• Piperazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Succinimides (pharmacology)
• Tropolone (analogs & derivatives, pharmacology)
• Ventral Thalamic Nuclei (cytology, physiology)