Characterization of Pharmacoresistance to Antiepileptic Drugs that Enhance GABAA Receptor-Mediated Inhibition in the Rat Li-Pilocarpine Model of Status Epilepticus
Abstract number :
3.175
Submission category :
Year :
2000
Submission ID :
1775
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Dorothy M Jones, Nadia Esmaeil, Robert L Macdonald, Univ of Michigan, Ann Arbor, MI.
RATIONALE: During status epilepticus (SE), there is a decrease in the effectiveness of diazepam to terminate the seizures. The development of pharmacoresistance to diazepam is related to the stage of SE. In the present study we investigated the stage-dependence of diazepam pharmacoresistance and determined if pharmacoresistance developed to two other commonly used anti-epileptic drugs (AEDs), phenobarbital and phenytoin, in the Li-Pilocarpine rat model of SE. METHODS: SE was induced in adult Sprague Dawley rats by intraperitoneal (i.p.) injection of 3 mmol/kg LiCl followed 20-24h later by i.p. injection of 50 mg/kg pilocarpine. Varying doses of diazepam, phenobarbital, or phenytoin were administered either 10 min. or 45 min. after pilocarpine, at the onset of stage 3 (S3) seizure activity, or 10 min. after the onset of S3 seizures. The animals were observed for at least 2h and behavioral recovery from status was determined. Recovery was defined as absence of forelimb clonus or falling, facial twitching, and stop and stare activity; in addition, resumption of normal behavior was required. RESULTS: Animals that were treated with diazepam before reaching S3 exhibited recovery in a dose-dependent manner, whereas animals that were treated after these stages exhibited both dose- and time-dependent recovery. Animals treated at the onset of S3 exhibited dose-dependent recovery, however animals treated up to 10 min. after their first S3 seizure progressively developed a pharmacoresistance at all doses tested. A similar relationship between stage, dose, and time was noted for phenobarbital; however, phenytoin did not suppress SE seizure activity at any time point or dose tested. CONCLUSIONS: Our results suggest a similar mechanism for development of pharmacoresistance to diazepam and phenobarbital. Our data are consistent with rapid modulation of GABAA receptors during SE that may result in pharamacoresistance to AEDs that enhance GABAA receptor mediated inhibition. Supported by NIMH 5T32 MH 1954(DJ)and NINDS NS 39479(RLM)