The development of tolerance to anticonvulsant drug effects
has traditionally been studied in terms of pharmacological
variables associated with the drug itself ; for example, the dose
or the schedule of administration. This type of tolerance is
referred to as pharmacologic drug tolerance. In contrast, we
have demonstrated that the development of tolerance to ethanol's
anticonvulsant effect is contingent upon the adminstration of
convulsive stimulation during periods of ethanol exposure; we
refer to this as contingent drug tolerance.
The purpose of the first two experiments in the present
thesis was to extend the phenomenon of contingent tolerance to
the anticonvulsant effects of three clinically relevant
antiepileptic drugs: carbamazepine (CBZ), diazepam (DZP), and
sodium valproate (VPA). In Experiment 1, kindled rats that
received an injection of CBZ (70 mg/kg, IP), DZP (2 mg/kg, IP),
or VPA (250 mg/kg, IP) 1 hr before each of 10 bidaily (one every
48 hr) convulsive stimulations displayed a significant amount of
tolerance to the drugs' anticonvulsant effects on the tolerance
test trial ; in contrast, there was no evidence of tolerance in
the rats from the three vehicle control groups. In Experiment 2,
the development of tolerance to the anticonvulsant effects of
CBZ, DZP, and VPA, administered on a bidaily basis, was shown to
be contingent upon the administration of convulsive stimulation
during the periods of drug exposure. Kindled rats in the three
drug-before-stimulation groups rapidly developed tolerance to the
anticonvulsant effects of CBZ, DZP, and VPA; in contrast, there
was no evidence of tolerance i n the respective drug-afterstimulation
groups, despite the fact that they had the same drug
history.
The purpose of the final three experiments was to compare
contingent and pharmacologic tolerance to the anticonvulsant
effects of DZP. Experiment 3 replicated earlier demonstrations
of pharmacologic tolerance to DZP's anticonvulsant effect;
kindled rats that received chronic DZP (2 mg/kg, every 8 hr, for
10 days) developed tolerance to the drug's anticonvulsant effect
even though they did not receive convulsive stimulation during
the periods of drug exposure. In Experiment 4, the rate of
dissipation of pharmacologic and contingent tolerance to DZP's
anticonvulsant effect was compared. Pharmacologic tolerance
gradually dissipated over the 16-day retention interval ; in
contrast, there was no evidence of dissipation of contingent
tolerance after 16 days of drug withdrawal. These data suggest
that different physiological changes are responsible for
pharmacologic and contingent tolerance to DZP's anticonvulsant
effect. This conclusion was supported by the results of
Experiment 5, in which a single injection of the benzodiazepine
receptor antagonist RO 15-1788 24 hr prior to a tolerance-retention
test trial significantly reduced the expression of
pharmacologic tolerance, but not contingent tolerance, to DZP's
anticonvulsant effect.
The results of these five experiments make two general
points. First, concurrent convulsive stimulation can have an
important effect on the development of tolerance to the
anticonvulsant effects of antiepileptic drugs. And second, there
are significant differences in the physiological changes
responsible for the development and the dissipation of contingent
and pharmacologic tolerance to DZP's anticonvulsant effect.
Because traditional theories do not address these differences, a
new model of contingent and pharmacologic tolerance is presented. / Arts, Faculty of / Psychology, Department of / [title page not included] / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/31438 |
| Date | January 1990 |
| Creators | Mana, Michael Joseph |
| Publisher | University of British Columbia |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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