Biomedical subjects

H Kalant

Publications and source records attributed to H Kalant.

At least 55 records · Page 3Linked to original sources

PubMed1992

Differential development of acute tolerance to the motor impairment and anticonvulsant effects of ethanol.

The development of acute tolerance to the motor impairment and anticonvulsant effects of ethanol was examined. Acute tolerance to the motor impairment effect of ethanol was shown by a decrease in the degree of intoxication, as measured on the moving belt task, at higher blood ethanol levels ranging from 206 to 256 mg/dl. There was no evidence of acute tolerance to the anticonvulsant effect of ethanol in rats tested over the same time period. These results indicate that, like chronic tolerance, acute tolerance to ethanol develops at different rates for different effects of the drug. The fact that chronic tolerance to the anticonvulsant effect of ethanol has been well documented raises doubts about the assumption that similar physiological changes underlie acute and chronic tolerance to a drug effect, and support the idea that the relationship between acute and chronic tolerance is more complex than previously thought.

Amygdala↗

PubMed1992

Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance.

Hypothermia and motor impairment (tilt-plane) tests were used to assess the phenomenon of rapid tolerance to ethanol and cross-tolerance to various alcohols, benzodiazepines, and barbiturates that differ in lipid:water partition coefficients. The hypothermic and motor impairment responses to ethanol were significantly reduced on day 2 in rats receiving ethanol (2 doses of 2 g/kg each for the hypothermia test and 2.3 and 1.7 g/kg for the tilt-plane test) 24 and 22 h earlier compared to the control group pretreated with saline. Ethanol pretreatment resulted in rapid cross-tolerance, on both tests, to the various alcohols (n-propanol, n-butanol, and t-butanol) and the benzodiazepines (chlordiazepoxide, diazepam, oxazepam, and flurazepam) tested. Ethanol pretreatment also conferred clear rapid cross-tolerance to barbital and phenobarbital, but did not result in rapid cross-tolerance to pentobarbital, secobarbital, amobarbital, or thiopental. The results on rapid cross-tolerance on both tests seen in these studies parallel the results obtained in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.

Alcohols↗

PubMed1992

Arginine-8-vasopressin potentiates acute ethanol intoxication.

AVP maintains ethanol (EtOH) tolerance after cessation of chronic EtOH treatment. However, the acute interaction of AVP and EtOH has not been well characterized. Rats were trained on a moving belt and the EtOH dose-response relationship (range 1.0-2.0 g/kg) was determined after pretreatment with saline, AVP (2.5-40 micrograms SC or 10 ng ICV), the AVP-V1 receptor antagonist [Des-Gly9,d(CH2)5(1),O-Et-Tyr2, Val4,Arg8]-vasopressin (10 ng ICV), or AVP in combination with the V1 antagonist. AVP produced a 16% decrease in the EtOH ED50 when given either SC or ICV; this decrease, which appears to represent true potentiation rather than additivity, was prevented by the preadministration of the V1 antagonist. Other rats were made EtOH-tolerant by 7 daily injections of either EtOH alone (1.8 g/kg IP) or EtOH (1.5 g/kg IP) + AVP (10 micrograms SC), followed by a practice session on the moving belt. In both sets of tolerant animals, AVP potentiation of acute EtOH effects was still seen on day 6. The mechanism of AVP potentiation of EtOH-induced impairment is unknown, but the failure of the V1 antagonist alone to alter the effect of EtOH suggests that endogenous AVP is not involved directly in modulating EtOH intoxication.

Alcoholic Intoxication↗

PubMed1992

Ketamine retards chronic but not acute tolerance to ethanol.

Motor impairment (tilt-plane test) was used to investigate whether the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine prevents the development of chronic and acute tolerance to ethanol. Rats were treated with ethanol or saline in the presence and absence of ketamine (separate groups) for 10 days and tested for ethanol tolerance in the absence of ketamine on the fifth and tenth days. In other studies, the effect of ketamine on acute tolerance to ethanol was examined. Rats that received ethanol daily without ketamine showed significant tolerance to ethanol on days 5 and 10, but those receiving ethanol plus ketamine daily showed significantly less tolerance to ethanol. Thus, ketamine interfered with the development of chronic tolerance just as it had been found previously to prevent rapid tolerance. In contrast, ketamine failed to block acute tolerance to ethanol. These results would suggest that the phenomena of acute tolerance and chronic tolerance have differences not previously reported.

Animals↗

PubMed1992

Effect of (+)MK-801 and ketamine on rapid tolerance to ethanol.

The motor impairment (tilt-plane test) responses to ethanol were significantly reduced on days 2, 3, 4, or 5 in rats receiving ethanol (2.3 and 1.7 g/kg) 24 and 22 h earlier, compared to the control group pretreated with saline. Administration of (+)MK-801, prior to behavioral testing with ethanol on day 1, inhibited the development of tolerance on all these days. Tolerance and the inhibitory effect of (+)MK-801 could no longer be seen if the second injection of ethanol was given on day 7, 8 or 11. Administration of (+)MK-801 on day 1 but after behavioral testing with ethanol did not block the development of rapid tolerance to ethanol on day 2. Administration of another commonly employed NMDA antagonist, i.e., ketamine, prior to ethanol on day 1, also blocked the development of rapid tolerance to ethanol. The findings suggest that NMDA antagonists block rapid tolerance by preventing some adaptation that occurs during intoxicated practice.

Analysis of Variance↗

PubMed1992

Potentiation of gamma-aminobutyric acid-mediated chloride flux by pentobarbital and diazepam but not ethanol.

The influx of 36Cl- into cerebral cortical and cerebellar microsacs from ICR mice and Sprague-Dawley rats was studied in incubations lasting 3 s, 500 ms, or 21 ms. In the 3-s assay, 10-40 mM ethanol did not affect either basal or gamma-aminobutyric acid (GABA)-mediated Cl- flux, at any GABA concentration tested. Only at a concentration of 600 mM did ethanol potentiate Cl- flux in both mouse and rat preparations. Ethanol (20 mM) also did not affect the significant potentiation of GABA-mediated flux produced by 50 microM pentobarbital or 2 microM diazepam in ICR mouse microsacs. In 21- and 500-ms incubations (quench-flow method), 50 microM pentobarbital significantly potentiated GABA-mediated Cl- flux in rat cortical microsacs, but 10-50 mM ethanol did not. These studies suggest that some as yet unrecognized factor is essential for ethanol enhancement of GABA-mediated Cl- flux, as reported by others in brain homogenates and in tissue culture.

Animals↗

PubMed1992

Role of the gamma-aminobutyric acid receptor/chloride channel complex in tolerance to ethanol and cross-tolerance to diazepam and pentobarbital.

The role of the gamma-aminobutyric acid (GABA) receptor/chloride channel complex in the development of tolerance to ethanol and cross-tolerance to diazepam and pentobarbital was assessed. Rats given a low (1.8 g/kg) dose of ethanol before daily practice on the moving belt test of motor incoordination, and those given a high daily dose (3.6 g/kg) not paired with practice, showed tolerance to ethanol and cross-tolerance to diazepam and pentobarbital, whereas rats receiving 1.8 g/kg of ethanol after practice did not. Control rats were trained on the moving belt, but received no ethanol treatment. No differences were seen among the treatment groups in the abilities of GABA or ethanol to increase 36Cl uptake into cerebral cortical microsacs. However, diazepam potentiation of GABA-mediated chloride flux was significantly lower in rats receiving daily intoxicated practice, but only if they received an i.p. injection of ethanol 1 hr before sacrifice. The degree of pentobarbital potentiation of the effect of GABA did not correlate with the behavioral cross-tolerance observed. The results indicate that behaviorally augmented cross-tolerance from ethanol to diazepam correlates incompletely with changes on the biochemical level.

Animals↗

PubMed1992

Effects of chronic treatment with ethanol on the development of cross-tolerance to other alcohols and pentobarbital.

The development of cross-tolerance to various alcohols and pentobarbital was examined in ethanol (EtOH)-treated mice. Chronic EtOH treatment (dosage rising in steps from 3.5-4.5 g/kg i.p. daily during a 23-day period) produced tolerance to its hypnotic effect. Such tolerance was seen as a reduction in the duration of loss of righting reflex (LRR), as well as higher blood EtOH levels at the offset of LRR, in EtOH-treated mice as compared to saline-treated controls. Cross-tolerance was shown by shifts in dose-response curves for the LRR induced by n-propanol and t-butanol. Such treatment, however, did not confer functional cross-tolerance to n-butanol and pentobarbital. Because n-butanol and pentobarbital are more lipid-soluble, whereas EtOH, n-propanol and t-butanol have low degrees of lipid solubility, the development of cross-tolerance among these sedative-hypnotic drugs might be related to their relative degrees of lipid solubility.

1-Butanol↗

PubMed1991

Arginine8-vasopressin potentiates the motor incoordinating effects of pentobarbital.

Arginine8-vasopressin (AVP, 10 micrograms), injected s.c., potentiated the motor-impairing effects of pentobarbital (10-20 mg/kg) injected i.p. in rats 1 h after AVP. Motor incoordination was assessed on the moving belt task. However, AVP (0.1-100 nM) failed to enhance pentobarbital potentiation of GABA-mediated 36Cl- uptake in rat cerebral cortical or cerebellar microsacs. There was also no effect of a 10 micrograms s.c. injection of AVP 1 h before killing, on pentobarbital potentiation of GABA-mediated chloride flux in either cerebral cortical or cerebellar microsacs.

Animals↗

PubMed1991

Differences among effects of sedative-hypnotic drugs on GABA-mediated chloride flux: quench flow studies.

The effects of 40 microM pentobarbital (PB), 1 microM diazepam (DZ) and 50 mM ethanol (EtOH) on gamma-aminobutyric acid (GABA)-mediated chloride flux into rat cerebral cortical microsacs were studied during 50 ms incubations with 36Cl. A quench-flow machine was used, allowing for preincubations and incubation of precise duration. A 1 s preincubation with PB did not increase the already significant effect of PB on GABA-mediated flux during the 50 ms incubation, but the 1 s preincubation was necessary for showing the effect of diazepam. EtOH had no effect, whether or not it was added in the preincubation. When microsacs were preincubated with 32 microM GABA for 1 s, far greater potentiation of the GABA effect was seen when the PB was also present during the preincubation than when it was only introduced in the incubation. Preincubation with both DZ and GABA also had a greater effect than merely adding DZ into the incubation, after the preincubation with GABA. Ethanol had no effect when added either during or after the 1 s preincubation with GABA. The different effects of these sedatives on GABA-mediated chloride flux are strongly suggestive of different loci or mechanisms of action.

Animals↗

PubMed1991

Initial sensitivity, acute tolerance and alcohol consumption in Fischer 344 and Long Evans rats.

In separate groups of Fischer 344 and Long Evans rats, initial sensitivity and acute tolerance to ethanol were determined in a jumping test. Sensitivity measurements in each strain were carried out in separate subgroups at ethanol doses of 1.5, 2.0, and 2.5 g/kg IP. Similarly, acute tolerance was measured in different subgroups of each strain using the method of two successive doses of ethanol (2 + 0.4 g/kg; 2 + 0.7 g/kg and 2 + 1.0 g/kg, respectively). After completion of sensitivity and acute tolerance measurement, acute tolerance was then tested in all rats. Based on their acute tolerance values, they were divided into three groups: high, medium, and low. Two weeks after the last acute tolerance test, six rats from each group (i.e., the six highest and six lowest from the high and low acute tolerance groups, respectively, and six from the mid-range of the medium tolerance group) were tested for voluntary ethanol drinking in the limited access model. Long Evans rats had lower initial CNS sensitivity to ethanol-induced impairment of jumping performance than Fischer 344 rats. Long Evans rats also drank significantly more alcohol than the Fischer 344 but there was no significant difference in acute tolerance development between these two strains. Moreover, within each strain the rats differing in acute tolerance development (i.e., high, medium, and low) showed no difference in alcohol consumption. These results suggest that acute tolerance development is not the main determinant of differences in ethanol drinking.

Alcohol Drinking↗

PubMed1991

Learning factor in rapid tolerance to ethanol-induced motor impairment.

Exposure of male Wistar rats to a single moderate dose (1.7 g/kg, IP) of ethanol (EtOH), followed by intensive intoxicated practice on the moving belt apparatus (a total of 12 min during the first hour after EtOH injection), results in functional tolerance to the motor-impairing effects of a second dose given either 8 or 24 h later. In the absence of intoxicated practice, or after a considerably reduced opportunity for it (a total of 4 min during the first hour after EtOH injection), the same dose of EtOH fails to produce tolerance. Thus, not only the opportunity to practice, but also its extent and possibly its quality are important determinants in the rapid development of intersessional tolerance. In contrast to its rapidity of development, no significant loss of this tolerance is evident three weeks after the tolerance acquisition sessions.

Alcoholic Intoxication↗

PubMed1991

Tolerance to ethanol and cross-tolerance to pentobarbital and barbital in four rat strains.

Chronic ethanol treatment by gastric intubation conferred tolerance to ethanol-induced motor impairment and hypnosis in four different rat strains: Fischer 344, Long-Evans, Sprague-Dawley, and Wistar. Cross-tolerance to barbital was also observed in all strains after chronic treatment with ethanol. However, chronic ethanol treatment failed to produce cross-tolerance to pentobarbital-induced motor impairment and hypnosis in any of the four strains. The demonstration of cross-tolerance to barbital and the lack of it to pentobarbital after chronic ethanol treatment confirms and extends recent observations on the specificity of the site and/or mechanism of action of sedative-hypnotic drugs that differ in lipid solubility.

Animals↗

PubMed1991

Rapid tolerance as an index of chronic tolerance.

Hypothermia and motor impairment (tilt-plane test) were used to assess the phenomenon of rapid cross-tolerance between ethanol and pentobarbital in rats. The hypothermic and motor-impairment responses were significantly reduced on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. Ethanol pretreatment, however, did not result in rapid cross-tolerance to pentobarbital on either test. Pentobarbital pretreatment on day 1 resulted in rapid tolerance to pentobarbital on day 2. However, in contrast to the lack of rapid cross-tolerance to pentobarbital after pretreatment with ethanol, pentobarbital pretreatment clearly conferred rapid cross-tolerance to ethanol. Determination of ethanol and pentobarbital blood levels suggested that pharmacokinetic alterations did not contribute significantly to the observed rapid tolerance and cross-tolerance. The asymmetry of rapid cross-tolerance seen in these studies mimics the results obtained by us in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.

Animals↗

PubMed1991

NMDA antagonist inhibits rapid tolerance to ethanol.

To test whether N-methyl-D-aspartate (NMDA) receptors have a role in the development of ethanol tolerance, (+)MK-801, an NMDA antagonist, and (-)MK-801, an inactive isomer, were tested in a rapid tolerance paradigm. Results showed that (+)MK-801 blocked the development of rapid tolerance to ethanol in the tilt-plane and hypothermia tests, while (-)MK-801 was ineffective. Neither drug changed the blood ethanol levels in the treated and untreated animals. These data suggest that the known role of NMDA receptors in long-term synaptic facilitation may underlie the effect of learning in the development of tolerance to the motor-impairing and hypothermic effects of ethanol.

Animals↗

PubMed1991

Research on alcohol metabolism: a historical perspective.

The primary enzymatic steps in ethanol metabolism to acetaldehyde, acetate and CO2 + water have been known for many decades, but only a few clinical implications were recognized, such as the risk of malnutrition due to use of alcohol as a source of calories, and the use of disulfiram and other ALDH blockers in the treatment of alcoholism. In the last four decades, however, further understanding of alcohol metabolism has led to recognition of the changes secondary to altered NAD:NADH ratio; to ethanol oxidation by, and induction of, the microsomal cytochrome P450IIE1 system; to fatty acid ethyl ester formation; to the increase in hepatic O2 consumption; and to the formation of acetaldehyde-protein adducts and antibodies to these. This new knowledge has led to important progress in relation to the pathogenesis and treatment of alcoholic liver disease, and to potentially valuable new diagnostic procedures for detecting heavy drinking and incipient alcoholic tissue damage. These advances demonstrate strikingly how basic research into fundamental biological processes can yield important and unanticipated practical benefits.

Ethanol↗

PubMed1990

Drug policy: striking the right balance.

Drug policy should strike the right balance between reducing the harm done by psychoactive drugs and reducing the harm that results from strict legal prohibitions and their enforcement. It is concluded, from a cost-benefit analysis based on pharmacologic, toxicologic, sociologic, and historical facts, that radical steps to repeal the prohibitions on presently illicit drugs would be likely, on balance, to make matters worse rather than better. Specific recommendations are offered for ameliorating the dangers to users and to society that are posed by each addictive drug.

Caffeine↗

PubMed1990

Initial sensitivity, acute tolerance and alcohol consumption in four inbred strains of rats.

Initial sensitivity and acute tolerance to ethanol were determined in a jumping test in separate groups of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats, and of Dahl salt-sensitive (SS) and salt-resistant (SR) rats. One week later, voluntary consumption of ethanol was studied in all groups. SH rats were found to be more sensitive than WKY, but there was no difference in acute tolerance development between these two strains. SH rats, however, drank significantly more alcohol than the WKY in both the two-bottle choice paradigm and the limited access model. Similarly, SS rats drank significantly more alcohol than the SR rats, although SS rats were found to be more sensitive to ethanol than SR. There was again no difference in acute tolerance development between these two strains. These observations suggest that difference in alcohol consumption in these strains cannot be accounted for by significant differences in acute tolerance or in initial sensitivity to ethanol.

Alcohol Drinking↗