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.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU.2429/5367 |
| Date | 11 1900 |
| Creators | Kippin, Tod Edward |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Relation | UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/] |
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