Current trends in biomedical research on alcohol.
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Alcoholism↗
Biomedical subjects
H Kalant
Publications and source records attributed to H Kalant.
Effects of treatment dose and intoxicated practice on the development of tolerance to ethanol-induced motor impairment.
The effect of treatment dosage and intoxicated practice on the development of tolerance to the motor-impairment effect of ethanol was examined. Within the treatment regimen employed (1.5-3.5 g/kg daily for 31 days), tolerance to the motor-impairment effect of ethanol developed whether or not the animals had opportunity to practice while intoxicated. The rate and extent of tolerance development were related to the ethanol treatment regimen. Intoxicated practice resulted in an enhancement of tolerance only at low treatment dosage (1.5-2.5 g/kg). These findings emphasize the treatment regimen as a critical variable in determining the rate and extent of tolerance development and the influence of intoxicated practice on such tolerance development.
Alcoholic Intoxication↗
Retention of ethanol tolerance by desglycinamide-arginine-vasopressin occurs in the absence of changes in hippocampal serotonin synthesis.
Central tolerance to the effects of ethanol in rats can be prolonged beyond its normal time of disappearance by administration of vasopressin (AVP) or desglycinamide-arginine-vasopressin (DGAVP) after ethanol withdrawal. While the mechanism underlying this effect is unknown, we have reported that specific depletion of hippocampal serotonin (5-HT) prevents the prolongation of tolerance by DGAVP. The present study explored possible presynaptic interactions between DGAVP and 5-HT terminals in the hippocampus, in relation to tolerance retention. When administered acutely, DGAVP had no effect on the rates of hippocampal or septal 5-HT synthesis in naive rats, as assessed by the NSD 1015 method. Moreover, chronic DGAVP treatment that maintained tolerance did not change the in vivo rate of 5-HT synthesis in the hippocampus or septum. Similarly, no significant differences were found in the levels of hippocampal 5-HT or 5-HIAA. Septal 5-HIAA levels were slightly but significantly lower in ethanol-DGAVP than in ethanol-saline rats. While the lack of changes in hippocampal 5-HT synthesis argues against a presynaptic DGAVP-5-HT interaction, the possibility remains of a peptide modulation of 5-HT postsynaptic actions.
Animals↗
Simultaneous determination of biogenic amines and morphine in discrete rat brain regions by high-performance liquid chromatography with electrochemical detection.
A simple and sensitive method has been developed for the simultaneous determination of norepinephrine, epinephrine, dopamine, 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and morphine in discrete rat brain regions by reversed-phase high-performance liquid chromatography with electrochemical detection. Perchloric acid extracts of the tissue were directly injected into the chromatographic system. Each of these compounds gave a linear response over the range of 20-160 ng/ml cerebellar homogenate (0.4-3.2 ng on column). Recoveries of these compounds, added to the homogenates, were complete when compared with standards dissolved in perchloric acid. The average between-run coefficients of variation for all these compounds were lower than 7.4% over the range of 20-160 ng/ml, and the within-run coefficients of variation at 20 ng/ml were lower than 8.7%. The present method has been applied to a study of the effects of intraperitoneal administration of morphine on biogenic amines in several discrete rat brain regions.
Animals↗
Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide.
The acute administration of ethanol, pentobarbital and chlordiazepoxide impaired, in a dose-dependent manner, the performance of rats on the moving-belt and two-way shuttle-box avoidance tests. Administration of these drugs for three weeks resulted in tolerance to their motor-impairing effects. Tolerance to ethanol or pentobarbital was characterized by a parallel shift of the dose-response curve to the right. Tolerance to chlordiazepoxide, however, was of greater extent and was accompanied by an apparent flattening of the dose-response curve. Symmetrical cross-tolerance developed between ethanol and pentobarbital. On the other hand, while chlordiazepoxide treatment conferred full cross-tolerance to ethanol and pentobarbital, only partial cross-tolerance to chlordiazepoxide was observed following treatment with ethanol or pentobarbital. These results suggest that at least part of the tolerance to chlordiazepoxide depends on changes in specific benzodiazepine receptors and is independent of the tolerance associated with non-specific changes in the cell membrane.
Animals↗
Influence of ambient temperature on the development and maintenance of tolerance to ethanol-induced hypothermia.
The development of tolerance to the hypothermic effect of ethanol was examined during chronic ethanol treatment (5 g/kg PO daily) at various ambient temperatures (Ta). Tolerance to the hypothermic effect of ethanol, monitored at five-day intervals for 25 days, developed rapidly when ethanol treatment was carried out at 4 degrees C. On the other hand, rats receiving ethanol treatment at a Ta of 36 degrees C, at which they did not experience hypothermia, acquired tolerance more slowly, but achieved the same level of tolerance as other groups after 25 days of treatment. This cannot be accounted for by the repeated testing at 21 degrees C at five-day intervals, since it was also observed under a non-repeated testing condition. Once tolerance to the hypothermic effect of ethanol was acquired, termination of ethanol treatment resulted in the loss of tolerance, but mere prevention of the hypothermic effect of ethanol did not. These results suggest that tolerance still developed even though the organisms did not experience hypothermia during ethanol treatment. Therefore there appears to be a component of tolerance, that depends upon a direct cellular action of the drug, as distinct from the physiological consequences of that action. However, variation in the degree of physiological disturbance (hypothermia) during drug exposure can modulate the rate of development of this tolerance.
Adaptation, Physiological↗
Vasopressin-like peptides retain ethanol tolerance in the absence of changes in serotonin synthesis in limbic structures.
Central tolerance to the effects of ethanol in rats can be prolonged beyond its normal time of disappearance by administration of vasopressin (AVP) or desglycinamide-arginine-vasopressin (DGAVP) after ethanol withdrawal. While the mechanism underlying this effect is unknown, we have reported that specific depletion of hippocampal serotonin (5-HT) prevents the prolongation of tolerance by DGAVP. The present study explored possible presynaptic interactions between DGAVP and 5-HT terminals in the hippocampus, in relation to tolerance retention. When administered acutely, DGAVP had no effect on the rates of hippocampal or septal 5-HT synthesis in naive rats, as assessed by the NSD 1015 method. Moreover, chronic DGAVP treatment that maintained tolerance did not change the in vivo rate of 5-HT synthesis in the hippocampus or septum. Similarly, no significant differences were found in the levels of hippocampal 5-HT or 5-HIAA. Septal 5-HIAA levels were slightly but significantly lower in ethanol-DGAVP than in ethanol-saline rats. In vitro studies revealed, on the other hand, that addition of AVP to the incubation medium failed to affect the spontaneous and stimulated release of endogenous 5-HT from hippocampal slices. While the lack of changes in hippocampal 5-HT synthesis argues against a presynaptic DGAVP-5-HT interaction, the possibility remains of a peptide modulation of 5-HT postsynaptic actions.
5-Hydroxytryptophan↗
Tolerance to ethanol and cross-tolerance to pentobarbital and barbital.
A chronic regimen of ethanol by intubation, which produced clear tolerance to ethanol-induced hypothermia, ataxia and narcosis, produced only a marginal degree of cross-tolerance to these effects of pentobarbital. The lack of appreciable cross-tolerance to pentobarbital-induced hypothermia and ataxia was also observed over a wide range of test doses. However, cross-tolerance to barbital was observed after chronic treatment with ethanol. Increased rate of drug biotransformation did not contribute significantly to the observed tolerance and cross-tolerance. The difference in the extent of cross-tolerance between ethanol and the two barbiturates is consistent with the hypothesis that there is a degree of specificity in the sites of action of ethanol and other sedative-hypnotic drugs.
Animals↗
Metabolic and functional aspects of tolerance to chlormethiazole and cross-tolerance to ethanol in the rat.
Adult male rats were used to study tolerance to, and physical dependence on, chlormethiazole and cross-tolerance to ethanol. In sleeping time studies, chlormethiazole was given orally at a daily dose rising progressively from 100 to 175 mg/kg over a period of 1 month. The tolerance that developed appeared to be due to altered disposition of the drug rather than to decreased sensitivity of the CNS. In agreement with this conclusion, there was only minimal cross-tolerance to ethanol, and no detectable withdrawal reaction. In studies with the moving belt test, the rats were given chlormethiazole subcutaneously in a total dose of 200 mg/kg daily for 69 days. This resulted in an equivocal manifestation of tolerance on the moving belt test and a small, but significant, tolerance to the hypothermic effect of chlormethiazole. Only an equivocal manifestation of physical dependence was found. These findings suggest that tolerance to the hypnotic and hypothermic effects observed with these chlormethiazole treatment regimens was due to altered pharmacokinetics rather than to functional tolerance of the CNS.
Animals↗
Functional tolerance to chlormethiazole and cross-tolerance to ethanol in the rat: importance of test and mode of drug administration.
Tolerance to the effects of chlormethiazole on circular maze performance, and cross-tolerance to ethanol, were investigated in rats. Tolerance to chlormethiazole in the moving belt test was also measured in the same rats. Treatment with a total daily dose of subcutaneous chlormethiazole, 200 mg/kg, for 20 days produced clear tolerance to chlormethiazole and cross-tolerance to ethanol in the circular maze test. This treatment, however, failed to produce tolerance to chlormethiazole in the moving belt test. No evidence of physical dependence was found. In other studies, continuous intravenous infusion of chlormethiazole, 30-50 mg/kg/h for 9 days, resulted in clear functional tolerance to chlormethiazole and cross-tolerance to ethanol in the moving belt test. Similarly, chronic ethanol treatment, 4-6 g/kg daily for 3 weeks, resulted in functional tolerance to ethanol and cross-tolerance to chlormethiazole in the same test. These results indicate that the demonstration of functional tolerance to chlormethiazole and cross-tolerance to ethanol is dependent both on the sensitivity of the behavioural measurement tests employed, and on the degree of continuity of exposure of the central nervous system to the drug. It is concluded that, for doses that are equipotent in acute log-dose studies, chlormethiazole produces less tolerance and physical dependence than ethanol, perhaps because of a shorter half-life.
Animals↗
Basic pharmacology of ethanol-serotonin interactions.
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Alcohol Drinking↗
Ethanol tolerance and enhanced calcium/calmodulin-dependent phosphorylation of synaptic membrane proteins.
The chronic effects of ethanol on synaptic membrane proteins was studied in ethanol-tolerant rats. Synaptic plasma membranes and postsynaptic densities were prepared from homogenates of forebrain and incubated in vitro with [gamma-32P]adenosine triphosphate in the presence and absence of calcium and calmodulin. In ethanol-tolerant animals, enhanced phosphorylation of synaptic plasma membrane but not postsynaptic density proteins was demonstrated in the presence of calcium and calmodulin. These results suggest that the development of tolerance to ethanol may involve alteration in neuronal sensitivity to calcium.
Animals↗
Site of interaction of serotonin and desglycinamide-arginine-vasopressin in maintenance of ethanol tolerance.
Rats trained to walk in a moving belt apparatus were subjected to a partial (fornix-fimbria (FF] or total (fornix-fimbria + cingulum bundles (FF + CB] chemical denervation of the dorsal serotonergic afferent pathways to the hippocampus. After chronic alcohol treatment that resulted in tolerance development to the motor-impairing effects of ethanol, desglycinamide-arginine8-vasopressin (DGAVP) or saline treatment was started and the residual tolerance measured at several intervals after ethanol withdrawal. DGAVP administration resulted in a virtually complete retention of ethanol tolerance when given to sham-operated controls or FF-lesioned rats. The peptide treatment failed, however, to prolong tolerance in rats bearing a complete FF + CB lesion, that reduced serotonin (5-HT) levels in the hippocampus and overlying parietal cortex to 10 and 45% of controls respectively. These results suggest that the serotonergic innervation of these areas is necessary for the action of DGAVP in the maintenance of ethanol tolerance.
Alcoholism↗
Residual effects of chronic cannabis treatment on behavior in mature rats.
Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.
Animals↗
Differential sensitivity to ethanol, pentobarbital, and barbital in spontaneously hypertensive and normotensive Wistar-Kyoto rats.
Ethanol, pentobarbital, and barbital sleep times and blood levels on awakening were determined in female spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WK) rats. Ethanol-induced sleep times were significantly longer for SH than for WK and blood ethanol concentrations on awakening were significantly lower in SH than in WK rats. By contrast, pentobarbital and barbital sleep times for SH rats were significantly less than for WK rats and barbiturate blood levels at awakening were significantly higher in SH than in WK rats. No differences were observed between SH and WK rats with respect to the disappearance of ethanol, pentobarbital, and barbital from blood and in the apparent volume of distribution of these drugs. These observations suggest differential CNS sensitivity of the SH and WK rats to ethanol and barbiturates and provide additional support for the notion that there exist differences in the modes of acute action of these drugs.
Animals↗
Alpha 1-adrenergic receptor involvement in norepinephrine-ethanol inhibition of rat brain Na+ -K+ ATPase and in ethanol tolerance.
Norepinephrine (NE) sensitization of rat brain Na+ -K+ ATPase to ethanol (EtOH) inhibition appears to be mediated by alpha 1-adrenoreceptors, since it was reversed by prazosin and WB-4101 (alpha 1-receptor antagonists) in a concentration-dependent manner, but not by yohimbine and piperoxan (alpha 2-receptor antagonists). In addition, clonidine (alpha 2-agonist) and methoxamine (central receptor type uncertain) produced very little sensitization. Chronic EtOH administration to rats for 3 weeks produced tolerance to the hypothermic effect of test doses of EtOH (3 g/kg, i.p.) and a decreased inhibitory effect of NE + EtOH on the enzyme in vitro. This inhibition was still prevented by prazosin and WB-4101. However, the binding of tritiated WB-4101 and prazosin to brain membrane preparations from control and EtOH-tolerant rats revealed that the maximum number of binding sites (Bmax) and the dissociation constant (KD) of alpha 1-adrenoreceptors were decreased after tolerance development. These changes in numbers and binding properties of alpha 1-adrenoreceptors probably account for the decreased NE sensitization of the ATPase to EtOH inhibition in preparations from EtOH-tolerant rats.
Adrenergic alpha-Antagonists↗
The 1985 Upjohn award lecture. Tolerance, learning, and neurochemical adaptation.
Alcohol or drug tolerance has been viewed traditionally as a homeostatic response to a direct chemical action of the agent on the neuron. This concept has undergone major modification as a result of recent observations that behavioral and environmental factors can alter markedly the tolerance developed to the same drug regimen. Obligatory task performance under the influence of the drug, classical conditional stimuli in an environment habitually associated with drug administration, previous exposure to a tolerance-producing regimen, and environmental modification of the expression of the drug's effect can all influence dramatically the degree of tolerance produced by a given dosage. Attempts to identify possible cellular mechanisms of tolerance development are illustrated by a review of studies on the relations between ethanol tolerance and changes in the neuronal membrane Na+ -K+ ATPase and its interaction with ethanol and norepinephrine, hippocampal serotoninergic systems and their interaction with a vasopressin derivative, a membrane-bound calcium- and calmodulin- dependent kinase, and hypothalamic-hypophyseal endorphin-producing systems. None of these studies or other similar ones, whether correlational or interventional in nature, has yet provided full and credible explanations of the effects of behavioral and environmental factors on tolerance development. Finding such explanations is the major current challenge in the neurobiology of tolerance.
Adaptation, Physiological↗
Residual effects of prolonged cannabis treatment on shuttle-box avoidance in the rat.
Chronic oral administration of cannabis extract to rats was examined for its residual effects on shuttle-box avoidance learning. In experiment 1 avoidance learning was assessed in rats that had been tested previously on other behavioral tests. Chronic treatment (3 months) facilitated the learning of shuttle-box avoidance in cannabis-treated animals relative to vehicle controls. In experiment 2 very similar results were obtained in naive rats. These and other residual effects of chronic cannabis treatment are similar to the effects of hippocampal lesions.
Animals↗