Contingent and pharmacologic tolerance to the anticonvulsant effects of antiepileptic drugs
Creators: name: Mana, Michael Joseph
Publisher: name: University of British Columbia
Year: 2011

description: The development of tolerance to anticonvulsant drug effects has traditionally been studied in terms of pharmacological variables associated with the drug itself ; for example, the dose or the schedule of administration. This type of tolerance is referred to as pharmacologic drug tolerance. In contrast, we have demonstrated that the development of tolerance to ethanol's anticonvulsant effect is contingent upon the adminstration of convulsive stimulation during periods of ethanol exposure; we refer to this as contingent drug tolerance. The purpose of the first two experiments in the present thesis was to extend the phenomenon of contingent tolerance to the anticonvulsant effects of three clinically relevant antiepileptic drugs: carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA). In Experiment 1, kindled rats that received an injection of CBZ (70 mg/kg, IP), DZP (2 mg/kg, IP), or VPA (250 mg/kg, IP) 1 hr before each of 10 bidaily (one every 48 hr) convulsive stimulations displayed a significant amount of tolerance to the drugs' anticonvulsant effects on the tolerance test trial ; in contrast, there was no evidence of tolerance in the rats from the three vehicle control groups. In Experiment 2, the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA, administered on a bidaily basis, was shown to be contingent upon the administration of convulsive stimulation during the periods of drug exposure. Kindled rats in the three drug-before-stimulation groups rapidly developed tolerance to the anticonvulsant effects of CBZ, DZP, and VPA; in contrast, there was no evidence of tolerance i n the respective drug-afterstimulation groups, despite the fact that they had the same drug history. The purpose of the final three experiments was to compare contingent and pharmacologic tolerance to the anticonvulsant effects of DZP. Experiment 3 replicated earlier demonstrations of pharmacologic tolerance to DZP's anticonvulsant effect; kindled rats that received chronic DZP (2 mg/kg, every 8 hr, for 10 days) developed tolerance to the drug's anticonvulsant effect even though they did not receive convulsive stimulation during the periods of drug exposure. In Experiment 4, the rate of dissipation of pharmacologic and contingent tolerance to DZP's anticonvulsant effect was compared. Pharmacologic tolerance gradually dissipated over the 16-day retention interval ; in contrast, there was no evidence of dissipation of contingent tolerance after 16 days of drug withdrawal. These data suggest that different physiological changes are responsible for pharmacologic and contingent tolerance to DZP's anticonvulsant effect. This conclusion was supported by the results of Experiment 5, in which a single injection of the benzodiazepine receptor antagonist RO 15-1788 24 hr prior to a tolerance-retention test trial significantly reduced the expression of pharmacologic tolerance, but not contingent tolerance, to DZP's anticonvulsant effect. The results of these five experiments make two general points. First, concurrent convulsive stimulation can have an important effect on the development of tolerance to the anticonvulsant effects of antiepileptic drugs. And second, there are significant differences in the physiological changes responsible for the development and the dissipation of contingent and pharmacologic tolerance to DZP's anticonvulsant effect. Because traditional theories do not address these differences, a new model of contingent and pharmacologic tolerance is presented.