| Summary: | Tolerance has been shown to develop to the anticonvulsant effects of many different antiepileptic drugs. In some cases, tolerance to antiepileptic drug effects is so complete that the drugs become clinically ineffective, even at toxic doses. This is clearly problematic for the treatment of epilepsy. The purpose of this thesis was to identify and investigate factors that reduce tolerance to anticonvulsant drugs. Accordingly, Experiments 1 and 2 were designed to demonstrate potential strategies for preventing the development of tolerance to anticonvulsant drug effects, and Experiment 3 was designed to determine the time course of the effect of convulsive stimulations on the dissipation of tolerance to anticonvulsant drug effects. The recently proposed drug-effect theory of tolerance provided the theoretical framework for these experiments.
The purpose of Experiment 1 was to assess the effect of dose on the development of tolerance to pentobarbital. During the tolerance-development phase, amygdala-kindledrats received one of the following before each bidaily (one every 48 hr) stimulation: either the same high dose (50.0 mg/kg), the same low dose (10.0 mg/kg), a series of doses that increased progressively from 10.0 to 30.0 mg/kg, or the saline vehicle. The rats that received the ascending-dose regimen became significantly tolerant to the anticonvulsant effects of pentobarbital. In contrast, tolerance to the ataxic effects of pentobarbital was significantly greater in the rats that received the high-dose regimen.
The purpose of Experiment 2 was to test the generality of the results of Experiment 1 by assessing the effect of dose on the development of tolerance to the anticonvulsant effects of diazepam. As in Experiment 1, amygdala-kindled rats were exposed to either a high-dose regimen (10.0 mg/kg), a low-dose regimen (1.0 mg/kg), an ascending-dose regimen (from 1.0 to 3.0 mg/kg), or the saline vehicle during the tolerance-development phase. Again, the rats that received the ascending-dose regimen became significantly tolerant to the anticonvulsant effects, whereas those in the other groups did not. In addition, both the rats that received the ascending-dose regimen and the rats that received the high-dose regimen exhibited a withdrawal effect after the cessation of diazepam injections. The results of Experiments 1 and 2 suggest that the common clinical practice of starting epileptic patients off on a low dose of anticonvulsant medication and then gradually increasing the dose should be re-evaluated.
In Experiment 3, amygdala-kindled rats were first made tolerant to the anticonvulsant effects of bidaily injections of diazepam (2.5 mg/kg). This tolerance did not dissipate in rats that received no diazepam over either a 4-day, 8-day, or 16-day retention interval if they were not stimulated during this interval. In contrast, tolerance dissipated in rats that received bidaily stimulations during the retention interval, even if they received diazepam injections after each stimulation. These results confirm previous findings that the occurrence of convulsive stimulations in the absence of the anticonvulsant drug effect is a key factor in the dissipation of tolerance to anticonvulsant drug effects, and they provide the first systematic evidence concerning the time course of the dissipation--tolerance declined gradually over the entire 16-day retention period.
The results of these experiments make four important points. First, Experiments 1 and 2 provided evidence that commoly employed ascending-dose regimens facilitate the development of tolerance to anticonvulsant drugs. Second, Experiment I demonstrated that the effect of drug dose on tolerance development can be different for different effects of the same drug. Third, Experiment 3 confirmed that the cessation of drug administration alone does not cause the dissipation of tolerance to anticonvulsant drug effects. And fourth, all three experiments provided general support for the drug-effect theory of tolerance: the theory that functional drug tolerance is an adaptation to the effects of the drug on neural activity, rather than to drug exposure per se.
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