The relation between drug exposure and tolerance: contingent drug tolerance reexamined
Creators: name: Kippin, Tod Edward
Publisher: name: University of British Columbia
Year: 2009

description: The finding that the performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response is commonly referred to as contingent drug tolerance. Contingent tolerance is typically demonstrated in before-and-after design experiments. One group of subjects receives drug before the performance of the criterion response (drug-before-test condition) and a second group of subjects receives drug after the performance of the criterion response (the drug-after-test condition). The usual finding is that substantial tolerance develops in the drug-before-test condition, but no tolerance whatsoever develops in the drug-after-test condition. Such demonstrations of contingent tolerance have led to the drug-effect theory of tolerance: the theory that tolerance to a particular drug effect is an adaptive response to the experience of that particular drug effect. The purpose of this thesis was to clarify the relation between drug exposure, drug effects, and the development of tolerance. Several experiments have demonstrated that no tolerance whatsoever develops to anticonvulsant drug effects if convulsive stimulation is administered prior to each drug injection (drug-after-test condition), rather than afterwards (drug-before-test condition). Be that as it may, a different experimental design was used in Experiments 1 and 2 to show that small amounts of tolerance develop in the absence of concurrent convulsive stimulation. Rats that received either 3 intraperitoneal injections of diazepam (5.0 mg/kg) per day for 10 days (Experiment 1) or 1 gastric intubation of ethanol (5 g/kg) for 21 days (Experiment 2) were significantly more tolerant than vehicle controls; however, the tolerance could be detected only by a sensitive savings measure. The purpose of Experiment 3 was to test a novel interpretation for the inconsistency between Experiments 1 and 2 on the one hand and the repeated failure to observe tolerance to anticonvulsant drugs following drug exposure without concurrent convulsive stimulation in the drug-after-test condition of before-and-after experiments on the other. This hypothesis is that small amounts of tolerance do develop following each drug injection in the drug-after-test condition but that it is dissipated the next day by the convulsive activity experienced in the absence of the drug. To test this hypothesis, one group of amygdala-kindled rats received 15 diazepam injections (2.5 mg/kg) each before a convulsive stimulation, one group received 15 diazepam injections each after a convulsive stimulation, one group received 15 diazepam injections with no convulsive stimulation, and one group received 15 vehicle injections either with or without convulsive stimulations. The drug-before-stimulation rats developed substantial tolerance as has been frequently reported, and the hypothesis was confirmed by the finding that the drug-only rats developed tolerance significantly faster than the rats in the drug-afterstimulation group and the rats in the vehicle-control group. The results of these experiments make two important points. First, tolerance develops following drug exposure even when the criterion response is not performed during drug exposure —albeit substantially less than when it is performed. Presumably, this is because a few of the neural circuits that are active during a convulsion are spontaneously active following the drug administration. Second, the reason why the subjects in the drug-after condition display no evidence of tolerance is because the drug-free performance of the criterion response prior to each drug exposure causes any tolerance that has developed to dissipate.