Differential tolerance to the antipentylenetetrazol activity of benzodiazepines in flurazepam-treated rats.

Rats were treated for one week with flurazepam (FZP). After an additional two days with no treatment, each rat was injected with one of seven benzodiazepines (BZs). Several different doses of each BZ were evaluated. Ten min later, 100 mg/kg pentylenetetrazol (PTZ) was injected, IP, and convulsive activity was recorded. Rats treated for a week with FZP were tolerant to ataxia induced by each of the seven BZs tested. There was a dose-dependent anti-PTZ effect for each BZ. Whether or not tolerance to the anti-PTZ effect was found depended on the particular BZ used. Tolerance was found for four of the drugs: diazepam, clobazam, flurazepam and desalkylflurazepam. However, no tolerance was found to the anti-PTZ actions of midazolam, triazolam or clonazepam. Brain BZ levels were measured by the ability of brain extracts to displace specifically bound [3H]flunitrazepam in vitro. There was no significant effect of one week of flurazepam treatment. It was proposed that differences among BZs in their interactions with receptors allowed some to circumvent the mechanism responsible for tolerance to the anti-PTZ effect.