The role of the drug-effect contingency in the development of cross tolerence to anticonvulsant drug effects
Creators: name: Kim, Chang Kwon
Publisher: name: University of British Columbia
Year: 2010

description: It was recently demonstrated that tolerance develops to the anticonvulsant effect of ethanol on kindled convulsions elicited in rats by electrical stimulation of the amygdala, following each of a series of ethanol injections delivered on a bidaily schedule (once every 48 hr). The tolerance developed only when the convulsive stimulation was administered during the periods of ethanol exposure: subjects that received ethanol 1.5 hr before each convulsive stimulation demonstrated tolerance after just five ethanol injections; whereas, no tolerance was evident in subjects that received ethanol 1.5 hr after each stimulation. Such tolerance, which is not the inevitable product of drug exposure but is contingent upon the expression of the drug effect--the anticonvulsant effect in this case--has been termed contingent tolerance. In Experiment 1A, tolerance developed to the anticonvulsant effects of bidaily IP injections of phenobarbital (30 mg/kg), trimethadione (270 mg/kg) and clonazepam (0.40 or 0.35 mg/kg) delivered 1 hr before each convulsive stimulation. In Experiment IB, the rats tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily injections of carbamazepine (35 mg/kg, IP), administered 1 hr before each stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Thus, cross tolerance appears to be greatest between anticonvulsant drugs that are effective against a similar profile of clinical and experimental seizures and that have similar mechanisms of action. In Experiment 2A, tolerance developed to the anticonvulsant effect of bidaily pentobarbital (15 mg/kg, IP) injections only in those rats that received the drug 1 hr before the convulsive stimulation, but not in those rats that had received the drug 1 hr after each stimulation. Furthermore, those rats that had received the convulsive stimulations while under the influence of pentobarbital subsequently displayed a greater degree of cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) than those that had received the drug after each stimulation (contingent cross tolerance). Experiment 2B was the converse of Experiment 2A: contingent tolerance was demonstrated to ethanol and contingent cross tolerance to pentobarbital. This study provided the first unambiguous and bidirectional demonstration that the drug-effect contingency plays an important role in the development of cross tolerance. In Experiment 3, tolerance to the anticonvulsant effect of ethanol dissipated when bidaily pentobarbital (15 mg/kg, IP) injections were delivered 1 hr after each convulsive stimulation (contingent cross-dissipation of tolerance), but did not dissipate when it was delivered 1 hr before each stimulation. Thus, the drug-effect contingency was shown to be important in the dissipation of tolerance to one drug following the administration of another drug. In Experiment 4, different groups of rats received different doses of pentobarbital (10-50 mg/kg, IP) on a bidaily schedule 1 hr before the convulsive stimulation. Greater tolerance was found to the anticonvulsant effect of pentobarbital in rats that had received successively larger doses of the drug, none of which were large enough to suppress the convulsions, than those rats that were maintained on a high dose of the drug that completely suppressed the convulsions. The greater tolerance in the group that received successively greater doses was attributed to the fact that the convulsions were experienced in the drugged state. This study challenged the generally accepted view that tolerance develops more rapidly and to a greater extent with larger drug doses . This thesis provides the first unambiguous and systematic evidence of the role of the drug-effect contingency in the transfer of tolerance from one drug to another, and in the dissipation of tolerance to one drug following the administration of another. On the basis of the present experiments, several elaborations were proposed to the drug-effect theory of drug tolerance, which claims that tolerance develops to drug effects and not to drug exposure per se.