Contingent tolerance and cross-tolerance to anticonvulsant drug effects: Pentobarbital and ethanol

Abstract

Tolerance to the anticonvulsant effect of pentobarbital (15 mg/kg, i.p.) was developed in amygdala-kindled rats; it was found to be contingent upon the rats' receiving convulsive stimulations during the bidaily (once every 48 h) periods of pentobarbital exposure (Experiment IB; contingent tolerance). Furthermore, the subjects that received convulsive stimulations while under the influence of the bidaily pentobarbital injections subsequently displayed a greater degree of cross-tolerance to the anticonvulsant effect of 1.5 g/kg of ethanol than those that had received the drug after the stimulations (Experiment 2; contingent cross-tolerance). Finally, contingent tolerance to the anticonvulsant effect of ethanol was maintained when kindled rats received convulsive stimulations during, but not before, bidaily periods of pentobarbital exposure (Experiment 3; contingent cross maintenance of tolerance). These results suggest that the repeated manifestation of particular drug effects-anticonvulsant effects in this case-play an important role in the development of some forms of drug tolerance and in their transfer to other drugs.

A problem with the interpretation of before-and-after experiments of drug tolerance.

“…The performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response—demonstrations of this effect are commonly referred to as contingent drug tolerance (Carlton & Wolgin, 1971). For example, the development of tolerance to the anticonvulsant effects of ethanol, carbamazepine, diazepam, valproate, and pentobarbital is facilitated by the administration of convulsive stimulation during the periods of drug exposure (Kim, Pinel, & Roese, 1991; Mana, Kim, Pinel, & Jones, 1991; Pinel, Kim, Paul, & Mana, 1989; Pinel, Mana, & Renfrey, 1985).…”