Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

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

Rats were trained to discriminate an injection of cocaine, 5.0 mg/kg, from an injection of saline, using a two-lever choice paradigm: one lever was correct after cocaine injection, the other lever was correct after a saline injection. After training, cocaine and methamphetamine were generalized to the cocaine lever, but phenethylamine (PEA) was only partially generalized. Cocaine was injected every 8 hrs, 20.0 mg/kg, and the discriminability of 5.0 mg/kg was tested every other day. Redetermination of the cocaine generalization curve after 6 days of chronic administration showed a shift to the right, from an ED50 of 4.1 mg/kg in the pre-chronic condition to 10.0 mg/kg. Tolerance did not develop to the behavioral effects of cocaine, measured by time to the first reinforcement and response rate. There was cross-tolerance to methamphetamine; however, no evidence for cross-tolerance to PEA was obtained. Following the acquisition of tolerance, chronic administration of cocaine was terminated, and the discriminability of 5.0 mg/kg was tested every other day for loss of tolerance. After 8 days the ED50 returned to 5.0 mg/kg.

The mechanisms which account for the diminished responsiveness (tolerance) of an individual to a drug, as a result of prior exposure to that drug, are not yet fully understood. Recently, it has been suggested that drug tolerance is a learned adaptive response. This possibility was examined by studying the effect of ethanol on body temperature and behavioral thermoregulatory responses of Sprague-Dawley rats. Two major studies were conducted. The first study examined the initial dose-related effects of ethanol (1, 2, or 3 g/kg i.p.); the second study examined the effect of ethanol (2.5 g/kg i.p.) administered on 14 consecutive days. Rats were tested in a thermocline, a hollo plexiglass tube in which a linear temperature gradient (6-36°C) was established through local heating and cooling of opposite ends of the tube. The position of rats in the thermocline was detected by a series of infrared light emitting diodes and photocells. The body temperature of rats in the thermocline was transmitted by a temperature sensitive telemetry capsule surgically placed in the peritoneal cavity. Validation studies demonstrated that rats reliably responded to temperature cues within the thermocline. In the first experiment ethanol produced a dose-related decrease in body temperature. All rats following injection initially selected an ambient temperature cooler than baseline. Rats receiving control treatment or the high dose of ethanol eventually shifted to a warmer ambient temperature. Activity levels were depressed equally by all three doses of ethanol. In the second experiment tolerance developed to the hypothermic effect of ethanol. A diminished response to ethanol was evident by the second test day and was maximal by day 7. Ethanol treated rats selected a cooler ambient temperature than control rats throughout the 14 day period, and activity levels continued to be depressed by ethanol throughout the 14 days. On the fifteenth day all rats were given an injection of saline. Rats which had previously received daily ethanol injections exhibited a hyperthermic response to saline compared to control rats. These results suggest that ethanol altered the central control of thermoregulation by lowering and possibly broadening the thermoregulatory set point. There was evidence for a conditioned hyperthermic response, but not a learned behavioral response, which contributed to the tolerance development.

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.

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. / Arts, Faculty of / Psychology, Department of / Graduate

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Pharmacology & Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 131-159.

Tolerance to anesthetic drugs is mediated partially by homeostatic mechanisms that attempt to restore normal neural excitability. The BK-type Ca2+-activated K+ channel, encoded by the slo gene, plays an important role in this neural adaptation. In Drosophila, a single sedative dose of the organic solvent anesthetic benzyl alcohol induces dynamic spatiotemporal changes in histone H4 acetylation across the slo regulatory region and leads to slo induction and tolerance. Mutations ablating the expression of slo also block the acquisition of tolerance, whereas activating the expression of a slo transgene results in resistance to drug sedation. Moreover, artificially inducing histone acetylation with the histone deacetylase inhibitor causes similar acetylation changes, slo induction, and functional tolerance to the drug. Histone acetylation changes occur over two highly conserved non-coding DNA elements, 6b and 55b, of the slo control region. To investigate the function of these two elements, I generated individual knockout mutants by gene targeting. Both knockout alleles are backcrossed into the CS wild type background. The 6b element seems to repress slo induction after drug sedation, because the 6b knockout allele overreacts to the drug. Compared to the wild type, 6b knockout allele shows a much greater slo message induction after drug sedation, it also displays stronger enhancements in seizure susceptibility and following frequency. In addition, the 6b deletion causes a persistent tolerance for at least a month, while tolerance only lasts about 10 days in wild type flies. My investigation also indicates that the 55b element limits basal slo expression in muscle. Finally, to investigate if the particular histone acetylation spikes are required for drug-induced slo induction and tolerance, I tether the histone-modifying enzymes, HDAC or HAT, to the 6b and 55b DNA elements, respectively. I observe that the positioning of an HDAC on these two elements blocks drug-induced slo induction and the development of tolerance. Therefore, histone acetylation across slo control region is required for the activation of slo and the acquisition of tolerance. / text

Thesis (Ph.D.) -- McMaster University, 1997. / Includes bibliographical references (leaves 67-70). Also available via World Wide Web.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.