Abstracts

Classical benzodiazepines (BZs) are extremely efficacious anti-convulsants but suffer from a number of serious side effects. Sedation, amnesia and abuse potential all limit their use in a clinical setting. However, the main reason benzodiazepines are not more widely used to treat epilepsy is because their effects tolerate with chronic dosing. BZs bind to 4 subtypes of GABA-A receptor (those containing an [alpha]1, [alpha]2, [alpha]3 or [alpha]5 subunit in combination with a [gamma]2) and recent work has shown that the different functional properties of BZs can be assigned to certain subtypes. The subtype(s) that mediate the anti-convulsant and tolerance effects of BZs have not been studied in detail. Here we have investigated the properties of an [alpha]3-selective BZ agonist, TP003. Three seizure models were used: mouse pentylenetetrazol (PTZ), mouse maximal electroshock (MES) and rat amygdala kindling (AK). Mice were pre-treated with TP003 (0.3-5 mg/kg p.o.) and then 30 minutes later either dosed with 120 mg/kg s.c. PTZ or given a trans-auricular shock (20 mA, 100 Hz, 1.5 sec). Seizures were scored on a modified Racine scale for the PTZ and as protection from tonic seizures for the MES. For the amygdala kindling unilateral electrodes were implanted and daily stimulations were given to elicit AK. Once kindled to stage 5 seizures, TP003 (0.3-5 mg/kg p.o.) was administered 30 minutes before stimulation and behavioural and electrical seizure activity measured. The tolerance experiment involved daily dosing of TP003 or diazepam and stimulations were carried out 30 minutes after drug dosing. TP003 dose-dependently decreased PTZ, MES and AK seizures after acute dosing to a similar extent to that seen with the standard BZ diazepam. In the chronic dosing experiment TP003 was anti-convulsant on day 1 of testing, but by day 3 the anti-convulsant effects had largely tolerated. In contrast diazepam still produced a robust anti-convulsant effect. [alpha]3-selective BZ agonists display equivalent anti-convulsant efficacy to those of the non-selective BZ diazepam following acute dosing. However, like non-selective BZs, they show tolerance on chronic dosing. (Supported by Merck Sharp [amp] Dohme.)