The role of the response contingency in the development and dissipation of tolerance to ethanol's anticonvulsant effect
Creators: name: Mana, Michael Joseph
Publisher: name: University of British Columbia
Year: 2010

description: Ethanol blocks the seizures normally elicited in kindled rats by convulsive stimulation. Tolerance to this anticonvulsant effect rapidly develops following a series of ethanol injections delivered at 48-hr intervals only when convulsive stimulation is administered during the periods of intoxication. Subjects receiving ethanol 1 hr before convulsive stimulation demonstrate tolerance after just five tolerance-development trials, whereas there is little tolerance in subjects that receive ethanol 1 hr after each stimulation. Such tolerance is termed contingent tolerance because its development is contingent upon the occurrence of the criterion response (i.e., convulsive activity) during the periods of ethanol exposure. The purpose of this thesis was to clarify the nature of contingent tolerance to ethanol's anticonvulsant effect. The first three experiments were designed to determine whether any tolerance at all develops in rats that do not receive stimulation during periods of intoxication. The fourth experiment was designed to determine whether the dissipation of tolerance to ethanol's anticonvulsant effect is influenced by the response contingency. Experiment 1 tested the hypothesis that the development of tolerance in the ethanol-after condition might be detectable if a smaller treatment dose than that previously studied was used. The subjects that were Intubated with ethanol (either 2 g/kg or 5 g/kg) before stimulation on the five tolerance-development trials demonstrated substantial tolerance development, whereas there was little evidence of tolerance in the ethanol-after subjects. The purpose of Experiment 2 was to determine whether the ethanol-after subjects would develop tolerance if more than the customary number of treatment trials were administered. Rats that received ethanol (2 g/kg, intubated) before each stimulation demonstrated significant tolerance after just 5 tolerance-development trials, whereas there was little evidence of tolerance in the ethanol-after condition even after 20 trials. In Experiment 3, a sensitive multiple-trial test permitted the detection of tolerance to ethanol's anticonvulsant effect in the ethanol-after group. In the test phase, rats that had received 20 tolerance-development trials in which ethanol (1.5 g/kg, IP) was administered after each stimulation developed tolerance more quickly than rats that had received saline injections. However, even the results of Experiment 3 illustrate the importance of the response contingency in the development of tolerance to ethanol's anticonvulsant effect. The tolerance that developed in the ethanol-after rats was not apparent on the first test trial, and was detectable only as an acceleration in the development of tolerance when ethanol was administered before stimulation in a series of test trials. In contrast, significant tolerance is typically detectable in the ethanol-before condition after only 5 trials. In Experiment 4, the response contingency was shown to play a critical role in the dissipation of tolerance to ethanol's anticonvulsant effect. Tolerant rats that received no ethanol over a 14-day retention interval did not lose their tolerance if they were not stimulated during this period, whereas tolerant rats that continued to receive ethanol on the same bidaily schedule associated with tolerance development demonstrated a complete loss of tolerance if they were stimulated before, rather than during, the periods of intoxication. Accordingly, ethanol withdrawal was neither necessary nor sufficient for the dissipation of tolerance; the critical factor was the elicitation of seizures in the absence of ethanol. Together, the results of these experiments provide unequivocal evidence of the important role that the response contingency plays in both the development and dissipation of tolerance to ethanol's anticonvulsant effect, and they clearly illustrate the inadequacy of two traditional assumptions about drug tolerance: 1) that the development of tolerance to a drug's effects is a sole function of the pattern of drug administration, and 2) that its dissipation is a sole function of drug withdrawal.