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H Kalant

Publications and source records attributed to H Kalant.

At least 37 records · Page 2Linked to original sources
PubMed1996

Current state of knowledge about the mechanisms of alcohol tolerance.

Far from being a simple homeostatic response to the presence of ethanol in the brain, tolerance is now recognized as a complex process which can develop within various time frames (acute, rapid, chronic) and in which the drug interacts with various environmental and cognitive factors, including associative and operant learning. A major question is whether the acute form is an innate adaptive response, which is converted into the rapid and chronic forms by the action of these external influences. So far, all behavioral and neuropharmacological manipulations that alter chronic tolerance also modify rapid and acute tolerance in similar ways. These include lesions of serotonergic forebrain projections, blockade of NMDA-type glutamate receptors and calcium "L" channels, central or peripheral injection of vasopressin and blockade of vasopressin V1 receptors. Cytochemical and immunofluorescence studies, combined with use of retrograde tracers, indicate the existence of a septohippocampal circuit which may mediate the interactions of these diverse elements in the production and maintenance of tolerance. There is limited evidence that development of tolerance leads to increased consumption of ethanol in experimental animals, but the clinical significance of these findings remains to be proven.

Journal Article↗
PubMed1996

Development of alcohol tolerance in the rat after a single exposure to combined treatment with arginine8-vasopressin and ethanol.

A single i.c.v. injection of 100 ng of AVP, followed 30 min later by an i.p. injection of EtOH (1.8 g/kg) and three 2-min trials of motor-impairment testing on a moving belt, resulted in the development of tolerance to this effect of EtOH, that lasted up to 4 weeks. The rate of tolerance loss was not altered by daily injection of a V1 receptor antagonist, but pretreatment with a V1 receptor antagonist or cycloheximide prevented this AVP facilitation of the development of tolerance to EtOH-induced motor impairment. The destruction of serotonin neuronal terminals by i.c.v. injection of 5,7-dihydroxytryptamine also prevented the development of tolerance after a single exposure to AVP + EtOH, but the destruction of catecholamine terminals by i.c.v. injection of 6-hydroxydopamine did not prevent such tolerance. In contrast to the findings with motor impairment, no tolerance to EtOH-induced hypothermia and loss of righting reflex developed after a single combined AVP-EtOH treatment. The tolerance that develops after one treatment with AVP-EtOH is a functional rather than a dispositional tolerance, and shares many pharmacological properties with chronic tolerance to EtOH.

Animals↗
PubMed1995

Peripheral injection of arginine8-vasopressin increases Fos in specific brain areas.

Learned behaviors and tolerance to ethanol can be maintained by peripheral injection of arginine8-vasopressin (vasopressin) under conditions in which they would otherwise be lost. However, the sites of this action in the brain have not been clearly identified. Using a polyclonal antibody raised against Fos and Fos-like proteins, we have demonstrated increases in immunoreactive Fos and Fos-like proteins in the suprachiasmatic, supraoptic and paraventricular nuclei of the hypothalamus, and lesser increases in piriform cortex and amygdala, of the rat 2 h after a s.c. injection of vasopressin. Our results suggest that the exogenous vasopressin may exert its central action by activating a cellular immediate early gene in specific brain regions.

Animals↗
PubMed1994

Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: importance of intoxicated practice.

Recent studies from our laboratory have shown that NMDA antagonists ((+)MK-801 and ketamine) inhibit the development of both rapid and chronic tolerance to the motor-impairing (moving belt test) and hypothermic effects of ethanol. The present experiments were designed to determine a) the generality of this inhibition, by using a different test of motor function, the tilt-plane test, and b) the possible importance of the experimental paradigm (i.e., with and without intoxicated practice), for the effect of the NMDA antagonist on ethanol tolerance. Daily administration of ethanol 3.3 g/kg for 5 days produced the same degree of tolerance on this test, whether it was given as a single dose of 3.3 g/kg before the daily training session or as divided doses of 2.3 g/kg before and 1 g/kg immediately after the session. The inhibitory effect of a single dose of (+)MK-801 (0.25 mg/kg IP) on rapid tolerance did not last longer than 1 day. Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. Groups of rats received ethanol (3.3 g/kg) or saline, either before a daily practice session on the tilt-plane or after it.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interaction between N-methyl-D-aspartate (NMDA) and serotonin (5-HT) on ethanol tolerance.

Earlier work from this laboratory had shown that 5-HT is involved in the development of tolerance to ethanol, and that enhancement of 5-HT levels by L-tryptophan accelerated tolerance development. To explore the possibility that NMDA receptors are involved in the 5-HT effect on tolerance, we examined the effect of a noncompetitive N-methyl-D-aspartate (NMDA) antagonist [(+)MK-801] on the ability of L-tryptophan to enhance tolerance to the effect of ethanol on tilt-plane test performance by the rat. L-Tryptophan treatment resulted in the development of rapid tolerance to a dose of ethanol that failed to produce such tolerance by itself. However, prior administration of (+)MK-801 blocked the L-tryptophan effect on rapid tolerance development, in a dose-dependent manner. These results suggest that NMDA receptors are involved in the 5-HT enhancement of ethanol tolerance.

Analysis of Variance↗
PubMed1994

Selective involvement of central 5-HT2 receptors in the maintenance of tolerance to ethanol by arginine8-vasopressin.

Arginine8-vasopressin (AVP) has been shown repeatedly to affect learning and memory and to maintain tolerance to ethanol if the brain serotonin and catecholamine systems are intact. In the present study, 5,7-dihydroxytryptamine (5,7-DHT) was injected intracerebroventricularly to disrupt serotonergic projections from the raphe to the forebrain. This resulted in a marked decrease in 5-hydroxytryptamine (5-HT) immunoreactivity in the terminal areas of the septum and the hippocampus, but not in the serotonin-containing neuronal cell bodies in the raphe nuclei. In control rats, tolerance to the motor-impairing effects of ethanol lasted for only 5 days after the cessation of ethanol treatment but could be maintained indefinitely for as long as AVP was given. In the 5,7-dihydroxytryptamine-lesioned rats, AVP was unable to maintain the tolerance. Continuous intracerebroventricular infusion of 5-HT restored the ability of AVP to maintain ethanol tolerance in the lesioned rats. A selective 5-HT2 agonist (alpha-methylserotonin) was equally effective, and a 5-HT3 receptor agonist (2-methylserotonin) was slightly less effective, but the 5-HT1A agonist dipropylaminotetralin (8-hydroxy-dipropylaminotetralin) was totally ineffective in this respect. The results indicate selective involvement of brain 5-HT2 and possibly 5-HT3 receptors in mediating AVP maintenance of tolerance to ethanol but do not pinpoint their specific loci or roles.

5,7-Dihydroxytryptamine↗
PubMed1993

GABA and pentobarbital potentiation of chloride influx into microsacs is influenced by incubation time.

GABA-mediated chloride influx into rat cerebral cortical microsacs, and its potentiation by pentobarbital (PB), was studied in incubations lasting 50 or 3000 ms. The 3000 ms assays were carried out manually, while the 50 ms assays were performed in a quench flow machine. The EC50 of the GABA effect and the Hill coefficient were both lower at the longer incubation times. Percent increase of the effect of GABA (at EC30 concentration) by pentobarbital was greater in the 3000 ms than in the 50 ms incubations. Preincubation of microsacs with PB for 5 s before the 50 ms incubation with GABA, did not increase the effect of PB beyond that obtained by adding PB into the incubation only. This finding is consistent with earlier ones cited, which imply that only PB binding that occurs after GABA has bound can potentiate the effect of GABA, and suggests that the concentrations of PB and GABA required to enhance chloride influx in vivo may be higher than those commonly reported in the literature.

Animals↗
PubMed1993

Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801.

Previous studies indicated that learning and memory play important roles in the development of tolerance to ethanol. (+)-MK-801 has been shown to impair learning and might thus also block the development of tolerance to ethanol. To test this possibility, rats were trained to criterion on the moving belt, a complex motor coordination test. Acute i.p. injection of (+)-MK-801 (a non-competitive NMDA channel blocker) produced dose-related impairment on this test. A dose of 0.1 mg/kg, that had negligible effect by itself, potentiated the acute effects of ethanol. In a chronic experiment with different animals, half of the rats received (+)-MK-801 or saline daily, followed 30 min later by ethanol (1.8 g/kg i.p.) and three practice runs on the belt, and 1 h later a second dose of (+)-MK-801 or saline. The other half received the same drugs but ethanol followed the practice. (+)-MK-801 blocked the functional tolerance to ethanol in both groups when the pre-ethanol dose was 0.25 mg/kg, but not when it was 0.1 mg/kg. Tolerance to the effects of (+)-MK-801 itself did not occur over 2 weeks of treatment. These results suggest that NMDA receptors are involved in development of chronic tolerance to ethanol as shown previously with rapid tolerance.

Animals↗
PubMed1993

Effect of NMDA receptor antagonists on rapid tolerance to ethanol.

Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e., tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol had disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.

Animals↗
PubMed1993

Development of rapid tolerance to pentobarbital and cross-tolerance to ethanol on a motor performance test with intoxicated practice.

Male Wistar rats given a single moderate dose (1.7 mg/kg, IP) of pentobarbital (PB), followed by six trials on the moving belt apparatus during the next hour, showed tolerance to the motor-impairing effects of a second dose of 17 mg/kg given 24 h later. A control group that received saline before the first test showed the usual initial sensitivity when tested with PB 24 h later. Three weeks later, the first group showed cross-tolerance to the effects of ethanol (1.7 g/kg, IP) on the same test, while the second group did not. These findings support the suggestion that rapid tolerance is closely similar to chronic tolerance and that the contribution of intoxicated practice results in a long-lasting component that applies to cross-tolerance to ethanol on the same test.

Alcoholic Intoxication↗
PubMed1993

Effect of anisomycin on the development of rapid tolerance to ethanol-induced motor impairment.

Male Wistar rats given a single moderate dose (1.7 g/kg, IP) of ethanol (EtOH), followed by six trials on the moving belt apparatus during the next hour, showed functional tolerance to the motor-impairing effects of a second dose given 24 h later if the first EtOH was preceded and followed by an injection of saline. The same EtOH dose and intoxicated practice did not produce tolerance if the saline injections were replaced by two doses of anisomycin (60 mg/kg each, SC) 15 min before and 105 min after the first dose of EtOH. This finding suggests that rapid tolerance, like chronic tolerance, requires de novo synthesis of protein during a short period immediately related to the test experience.

Animals↗
PubMed1993

Effect of D-cycloserine on rapid tolerance to ethanol.

We recently reported that the noncompetitive NMDA antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present article, we show that D-cycloserine (CS), an agonist at the glycine site of the NMDA receptor that enhances learning and memory, also enhances the development of rapid tolerance to ethanol. Rats were pretreated on day 1 with saline or CS, followed 30 min later by ethanol (2.3 g/kg, IP) or saline. At the end of motor impairment testing on the tilt-plane apparatus, a second injection of CS (3 mg/kg, IP, each time) or saline was given, followed 30 min later by ethanol or saline. Ethanol pretreatment alone (at this dose) did not result in rapid tolerance to ethanol on day 2. However, the group pretreated with CS and ethanol on day 1 showed significant tolerance on day 2 compared to other groups. Pretreatment with CS on day 1 did not affect the motor impairment response to the first exposure to ethanol whether this was on day 1 or day 2. In another experiment, administration of (+)MK-801 (0.25 mg/kg, IP) prior to CS abolished the rapid tolerance enhancement by CS. These findings are further evidence that the NMDA system, which requires activation by the glycine receptor, plays a major role in the development of at least some forms of ethanol tolerance.

Animals↗
PubMed1993

Inhibition of nitric oxide synthesis impairs rapid tolerance to ethanol.

To examine whether nitric oxide was involved in the development of rapid tolerance to the motor-incoordinating effects of ethanol (tilt-plane test), three experiments were undertaken in a rapid tolerance paradigm in rats. The first experiment tested the effect of the nitric oxide synthase inhibitor, L-nitro-arginine, on the acquisition of ethanol tolerance. The second compared the effects of L-nitro-arginine with those of its inactive isomer, D-nitro-arginine. The third examined whether overload with the substrate L-arginine would prevent the action of L-nitro-arginine on rapid tolerance. The results demonstrated that L-nitro-arginine prevented the development of rapid tolerance, while D-nitro-arginine was ineffective. An excess of the substrate L-arginine reversed the inhibitory action of L-nitro-arginine on tolerance development. These data suggest that nitric oxide may play a role in the development of tolerance to ethanol. The role of nitric oxide in ethanol tolerance may be similar to its role in memory and learning, involving facilitation of transmission in certain NMDA synapses.

Animals↗
PubMed1993

Problems in the search for mechanisms of tolerance.

Recent evidence has cast some doubt on the GABA-activated chloride channel as a primary locus of action of ethanol, but strongly implicates the NMDA-receptor-linked cation channel. NMDA antagonists can prevent the development of tolerance to ethanol in various paradigms. However, explanation of the various time-frames of tolerance, and of the role of associative and instrumental learning in its development, requires consideration of probable interactions among NMDA, arginine vasopressin, serotonin 5-HT2, GABA and acetylcholine receptors. A possible locus of such interaction may be a loop involving medial and lateral septal nuclei and hippocampus. Synthesis of protein kinase C and other proteins may be a cellular mechanism of tolerance, as it appears to be in learning. Further clarification of the roles of these cellular mechanisms in tolerance requires detailed analysis of their interactions with the behavioral and environmental factors that markedly affect tolerance.

Adenosine↗
PubMed1992

Differential inhibition by NMDA antagonists of rapid tolerance to, and cross-tolerance between, ethanol and chlordiazepoxide.

We have recently found that the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present report we show that they also block rapid cross-tolerance from chlordiazepoxide to ethanol as well as ethanol to chlordiazepoxide. However, NMDA antagonists fail to block the development of rapid tolerance to chlordiazepoxide. Our results suggest that NMDA antagonists may affect not only the acquisition of rapid tolerance or cross-tolerance to sedatives but also the ability to express that tolerance or cross-tolerance, depending on the drugs used. It is also possible that the phenomena of rapid tolerance and rapid cross-tolerance have basic differences not previously reported in the literature.

Animals↗
PubMed1992

Formulating policies on the non-medical use of cocaine.

The formulation of policy on cocaine, as on any other social issue, involves explicit or implicit cost-benefit analyses with many factors. Cocaine use carries many medical, psychiatric and social risks, and its inherent pharmacological risk of dependence is greater than for other drugs. The reported frequency of these problems has increased exponentially over the past fifteen years. However, current levels of use are decreasing in the general population, though still increasing among certain subpopulations in which it is accompanied by violent crime. On the other hand, the attempt to control use mainly or exclusively by reducing the supply has been of low efficacy and extremely expensive, in both human and monetary terms, for the consuming countries and economically and politically devastating for the producing countries. Yet past experience with other drugs suggests that legalization of cocaine would increase its use substantially. Moreover, legalization runs counter to public sentiment, even in those countries where the law is applied leniently against users and small-scale traffickers. The most practical policy appears to be to maintain prohibition as a sign of social disapproval, but to rely much more heavily on non-coercive measures to reduce demand by strengthening public consensus against all drug use.

Cocaine↗
PubMed1992

Influence of intoxicated practice on the development of acute tolerance to the motor impairment effect of ethanol.

The influence of practice while under intoxication was tested on the development of acute tolerance to the motor impairment effect of ethanol. In experiment 1, the motor impairment effect induced by an IP injection of 1.8 g/kg ethanol was quantified after various intervals in separate groups of animals. Lower impairment scores were observed in rats tested at 30 and 45 min after ethanol administration than in those tested at 15 min. In group that was tested repeatedly after ethanol administration, intoxication decreased more rapidly and to a greater extent. The same phenomenon was observed in experiment 2 when a higher dose of ethanol (2.2 g/kg) and later testing (60-180 min after ethanol administration) were employed. To maintain constant blood ethanol levels, those tested at later times received a supplementary dose of ethanol. Impairment scores were lower in rats tested at later times than in those tested earlier. Again, the impairment scores for the practice group decreased more rapidly and to a greater extent. Blood ethanol levels among various groups were essentially the same. Acute tolerance to ethanol can develop without opportunity for practice while under intoxication. Intoxicated practice, however, can facilitate acute tolerance development.

Animals↗