Substance and alcohol actions/misuse最新文献

We have recently found decreased plasma tryptophan levels in alcoholics as well as in baboons and rats fed alcohol chronically. In the present study we investigated changes in tryptophan pyrrolase which is considered to be rate limiting for tryptophan catabolism. Rats fed alcohol chronically showed an increased activity of the enzyme in the liver and an increased formation of kynurenine after administration of a tryptophan load. It is concluded that this enhanced enzymatic activity may be responsible, at least in part, for the depressed plasma tryptophan levels we observed.

It has been found that a short period of severe intoxication with ethanol produces a marked reduction of adrenal catecholamines. Animals so treated demonstrate moderate to severe withdrawal signs. Accordingly, adrenal and urinary catecholamines were determined in rats undergoing withdrawal after treatment with several drugs known to modify sympathetic function. The depressant diazepam obtained withdrawal severity without altering peripheral catecholamines, propranolol reduced urinary catecholamines and transiently ameliorated withdrawal, whereas hexamethonium elevated urinary catecholamines and enhanced the severity of withdrawal. No drug treatment modified adrenal catecholamine levels. In this model the attenuation of adrenergic function has no consistent influence on the manifestation of withdrawal after ethanol.

Thin layer chromatography and chemical detection procedures for barbiturates are described and the reaction mechanism introduced. We show that by this technique barbiturates can be characterized as long, intermediate, short, and very short acting, with a few exceptions, by Rf value and by the typical spot color hue. The factors involved and chemical requirements for color are mentioned, e.g. 1. Behavior in organic solvents 2. Silica Gel polarity and pH 3. Functional groups responsible for interaction with the reagent 4. pH and chemicals of the color developer 5. Mechanism of reaction.

The reuptake characteristics of norepinephrine, gamma-aminobutyric acid (GABA), and choline were investigated in the long-sleep (LS) and short-sleep (SS) mouse lines. Kinetic analysis revealed no significant differences between lines in affinity (Km) or maximal velocity (Vmax) for norepinephrine and GABA measured in cortex and cerebellum or for choline measured in striatum and cortex. In vitro ethanol dose-response curves (0-1.7 M) for these neurotransmitters showed highly significant inhibition of reuptake except for reuptake of choline in cortex. All responses to ethanol were identical in both lines of mice. The magnitude of GABA reuptake inhibition was greater in cortex than in cerebellum. On the other hand, choline reuptake was very sensitive to ethanol in striatum, but was unaffected in cortex. These data suggest some regional specificity in ethanol's solubility. Inhibition of reuptake by ethanol concentrations greater than 0.86 M was determined to be irreversible and not due to hypertonic lysis. Our data are in complete agreement with previously published studies which suggest that ethanol inhibits neurotransmitter reuptake. However, since the LS and SS mice were selected for differential sensitivity to ethanol, and since we found no differences between lines in kinetic parameters or acute responses to in vitro ethanol, it appears that inhibition of neurotransmitter reuptake is not involved in the depressant effects of ethanol.

Bar-press responding of rats was maintained under a 30-response fixed-ratio schedule of food presentation. Responding was characterized by an initial pause followed by a high rate of responding which prevailed until food delivery. Oral administration (15 minutes pre-session) of ethanol (0.25-6.0 g/kg) or tertiary-butanol (0.25-3.0 g/kg) produced dose-related decreases in responding at the higher doses; tertiary-butanol was 1.6 times as potent as ethanol. The 3.0 g/kg dose of ethanol or the 1.0 g/kg dose of tertiary-butanol decreased responding by about twenty percent when given either 15, 30, or 60 minutes prior to the experimental session. Overall response rate and response rate exclusive of the initial pause were decreased similarly.

The effects of membrane composition on the sensitivity of membrane functions to ethanol in Escherichia coli have been investigated. The addition of ethanol (0.67M) in vitro did not cause appreciable inhibition of NADH oxidase, D-lactate oxidase or ATPase but caused an 11% to 30% inhibition of succinic dehydrogenase, glutamate uptake, proline uptake and 1ac permease. Although the sensitivities of some of these membrane functions to ethanol varied with membrane composition, none correlated with the changes in sensitivity to killing by ethanol. In contrast, leucine transport was resistant to ethanol (0.67M) in control cells and in cells enriched in vaccenic acid, but was inhibited by 25% in cells grown in palmitic acid. The release of nucleotides was examined as a comparative measure of cellular permeability. Ethanol increased nucleotide leakage. Leakage was reduced in cells grown in vaccenic acid and enhanced in cells enriched in palmitic acid. The addition of MgSO4 (10mM) reduced nucleotide leakage and enhanced survival. Based upon these results, metabolite leakage was proposed as the primary event associated with bacterial inactivation in buffered solutions of ethanol. The increase in acyl chain length is proposed as the beneficial aspect of vaccenic acid incorporation rather than the increase in membrane unsaturation.

Hepatic ethanol metabolism in the liver from carbon tetrachloride (CCl4)- treated animals was studied using non-recirculating hemoglobin-free liver perfusion system. CCl4-administration decreased ethanol uptake by the liver to 56% and 30% of the control values following the acute (24 hrs. after treatment) and chronic (8-12 weeks) treatments, respectively. In addition, 4 mM fructose, a well-known agent to increase ethanol metabolism in the liver, did not increase the hepatic uptake of ethanol in CCl4-treated livers. Hepatic alcohol dehydrogenase activity was not changed following acute and chronic CCl4 treatments. The lactate/pyruvate (cytosolic NADH/NAD) ratio as well as beta-hydroxybutyrate/acetoacetate (mitochondrial NADH/NAD) ratio significantly increased, whereas both hepatic oxygen uptake and oxidation of NADH in mitochondria remarkably decreased in parallel with the magnitude of liver injury induced by CCl4. Histological studies revealed that the liver had centrilobular coagulative necrosis with fatty droplet formations at acute phase, while bridging fibrosis between central and portal areas and the pattern of cirrhosis with conspicuous changes in the mitochondria were seen at chronic phase. These data indicate that CCl4-treatment significantly reduces hepatic ethanol metabolism via the inhibition of reoxidation of NADH, a rate limiting step of ethanol metabolism in the liver.

We have examined the relationship between membrane fluidity and the alcohol-induced loss of righting reflex at different temperatures using the fish Gambusia affinis. The potency of ethanol and hexanol increased dramatically with temperature. Ethanol-induced narcosis could be antagonized by a reduction in incubation temperature. Both an increase in temperature and the addition of ethanol caused an increase in membrane fluidity. However, membrane fluidity itself did not correlate with narcosis and was primarily determined by incubation temperature. Narcotic concentrations of ethanol caused a change in fluidity equivalent to less than that caused by a 2 degree increase in temperature while an 8 degree increase in temperature did not induce narcosis. From these studies, we conclude that the ethanol-induced increase in bulk membrane fluidity as measured by diphenyl-hexatriene is not the causal event for narcosis although the magnitude of this change does correlate with the alcohol sensitivity. We have also examined the effects of temperature adaptation on the sensitivity of these animals to ethanol. Summer animals contained higher levels of saturated fatty acids, exhibited a higher temperature range than winter animals and were more resistant to ethanol, providing further evidence for membrane structure as a determinant of alcohol sensitivity.

Discrepant results have been reported from different laboratories on the effects of tetrahydropapaveroline (THP) and related compounds. In order to try to explore the discrepancy, an independent researcher participated in a partial replication attempt at the laboratory from which reports had previously come that THP markedly increased ethanol consumption by rats and produced withdrawal-like behavior. Withdrawal-like signs were observed after several once-daily bilateral ventricular infusions of 1.0 microgram THP. These abnormal behaviors varied in frequency and intensity but continued up to the last day of infusion and were rated independently by up to 5 judges. The mean ethanol intake, however, during THP treatment remained virtually the same as before THP (mean g ethanol per kg body wt. +/- SE: 1.60 +/- 0.29 before THP, 1.69 +/- 0.45 during THP). Control rats drank similar amounts of ethanol (1.60 +/- 0.33 before vehicle infusions, 1.65 +/- 0.42 during vehicle infusions). The individual THP animals tended to show greater variations than the controls from their own pre-treatment levels, but none of them showed a mean increase of greater than 2.0 g/kg in ethanol intake. Injections of THP or noreleagnine into cannulae aimed at hippocampal and periventricular grey sites also failed to increase alcohol drinking; however because histology was not available, it is not known whether or not the sites of injection were located in these structures. In comparison to the previously published report of Myers and Oblinger (25), this experiment differed in several variables. It is concluded that the precise experimental parameters necessary for once-daily THP reliably to increase ethanol consumption remain to be determined.