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Biomedical subjects

R A Deitrich

Publications and source records attributed to R A Deitrich.

At least 55 records · Page 3Linked to original sources
PubMed1990

Development of central nervous system sensitivity to ethanol and pentobarbital in short- and long-sleep mice.

Dose-response curves to ethanol from day 9 to adulthood have been carried out in short-sleep and long-sleep mice. At very young ages, up to about 35 days of age, the mice differ in sleep time response to ethanol, but this difference is due to the development of acute tolerance. At older ages the differences in sleep times are due to a combination of acute tolerance and differences in initial sensitivity. In contrast to adult mice, that show no difference in brain sensitivity to pentobarbital, short-sleep mouse pups ranging in age from days 9 to 12 are more sensitive to pentobarbital than are long-sleep mice. The difference in sensitivity at young ages is again due to differences in development of acute tolerance and not to initial sensitivity differences. It is postulated that the development of acute tolerance to ethanol is rapid, within minutes, following injection of ethanol and that the system responsible might be the gamma-amino-butyric acid-mediated chloride flux which has also been shown to develop tolerance within 5 min after ethanol injection.

Aging↗
PubMed1989

Investigations of the role of protein kinase C in the acute sedative effects of ethanol.

The activity of protein kinase C (PKC) in whole brain and brain areas of mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute ataxic effect of ethanol has been investigated. The cytosolic and membrane fractions of whole brain PKC activities are significantly less in LS mice than in SS mice. There are significant differences in PKC activity between brain areas in both the SS and LS lines. Ethanol given in ataxic doses results in significantly increased amounts in PKC activity in whole brain cytosolic fractions and in some brain areas but equally in both SS and LS mice. Ethanol added in vitro reduced enzyme activity slightly in SS brain membranes, suggesting that the mechanism of the increase in PKC activity seen after in vivo administration is indirect. These results indicate that PKC is not involved in the mechanism whereby LS and SS mice differ in alcohol sensitivity. Direct intracerebroventricular (ICV) injection of phorbol myristate acetate (PMA), an activator of PKC, resulted in increased sleep times in both SS and LS mice. ICV injection of PMA also caused a more marked decrease in body temperature in LS than in SS mice. The half-life of PMA in brain was determined to be 9.6 hr and no metabolites could be detected. At limiting calcium concentrations, PMA added in vitro activated PKC equally well in both lines. However, PMA given ICV did not alter the level of PKC as determined in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Brain ascorbic acid levels: mice and rats selected for differences in acute reactions to ethanol.

There are variations of ascorbic acid levels in different brain areas of mice and rats. However, there are no differences in ascorbic acid levels between lines of mice selectively bred for differences in ethanol sensitivity for 25 generations. Thus, it is unlikely that brain ascorbic acid plays a significant role in the acute sedative effects of ethanol in these mice. Studies with inbred strains of mice known to differ in ethanol preference, acute sensitivity and withdrawal sensitivity also failed to reveal any differences in brain ascorbic acid levels. There were differences in ascorbic acid content between selectively bred lines of rats in various brain areas at generation five of selection.

Animals↗
PubMed1987

Effects of chronic ethanol exposure on adenylate cyclase activities in the rat.

The effects of chronic ethanol administration on striatal and cerebellar adenylate cyclase systems were investigated in the rat. The chronic ethanol treatment resulted in behavioral tolerance, but no difference in the sensitivity of adenylate cyclase to in vitro ethanol was observed. In one set of experiments using 173-195 g rats, GTP-, dopamine- and NaF-stimulated adenylate cyclase activities in the striatum were higher in rats chronically treated with ethanol when compared to animals pair-fed the liquid diet. However, no difference in adenylate cyclase activity was observed in cerebellar or striatal tissues when larger rats (280-385 g) were used. In conclusion, an adaptive change in activation of adenylate cyclase by in vitro ethanol does not occur after chronic ethanol treatment. The observed changes in enzyme activity measured in the absence of in vitro ethanol do not appear to be a simple, direct effect of chronic ethanol treatment.

Adenylyl Cyclases↗
PubMed1987

Relationship between acute ethanol-related responses in long-sleep and short-sleep mice.

Long sleep (LS) and short sleep (SS) lines of mice were derived from a heterogeneous stock of mice (HS) and have been selectively bred on the basis of the time the animals were devoid of the righting reflex (sleep time) following acute ethanol administration. We have tested a large group of the HS mice for sleep time response to ethanol. Animals were then selected from the extremes of the HS sleep time response and designated short sleep (HS-SS) or long sleep (HS-LS). The ED50 value for loss of righting reflex was compared between these mice (HS-SS and HS-LS) and animals that had undergone 25 generations of selection (SS and LS mice). The ED50 value was not significantly different for the HS-LS (1.9 g/kg) and LS (2.17 g/kg) mice but was markedly different between HS-SS (3.02 g/kg) and SS (4.21 g/kg) mice. The ED50 values for the eight inbred strains that constituted the HS stock ranged only from 2.33 to 2.78 g/kg. The value for LD50 one hour after ethanol administration was found to be 9.03 g/kg and for SS mice 6.94 g/kg for LS mice, in contrast to our previous findings of no difference in LD50 values between SS and LS mice when ascertained 24 hr after the ethanol dose. Since the two lines were selected only for a sleep time difference, a differential sensitivity to other consequences of acute ethanol exposure, such as the lethal dose, would not be expected unless the effects shared a common genetic mechanism of action with ethanol sleep time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Specificity of the action of ethanol in the central nervous system: behavioral effects.

The specificity of ethanol's behavioral actions is reviewed with regard to the possibility of other molecules, derived from ethanol sharing that action. The specificity of ethanol in relationship to other drugs with similar behavioral actions is also briefly reviewed. It is concluded that the ethanol molecule itself is primarily responsible for the behavioral effects but that other compounds may contribute to the effects. Ethanol is seen as being more unique than previously thought in that it has behavioral actions that are not the same as gaseous anesthetics.

Animals↗
PubMed1986

Effects of induction of rat liver cytosolic aldehyde dehydrogenase on the oxidation of biogenic aldehydes.

Phenobarbital and tetrachlorodibenzo-p-dioxin (TCDD) induce two different forms of aldehyde dehydrogenase (EC 1.2.1.3, ALDH), designated phi and tau respectively, in the rat liver cytosol. The physiological substrates for these enzymes are as yet unknown. In this study we investigated whether the induction of these enzymes forms affected the metabolism of dopamine and norepinephrine in rat liver slices. A 10-fold increase in phi-ALDH produced by phenobarbital treatment resulted in small increases in the formation of 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxymandelic acid from the biogenic amines. The 50- to 100-fold elevation of the tau-isozyme did not alter the rate of formation of the acids. When liver slices were incubated with 40 mM ethanol, the formation of the reduced products of dopamine and norepinephrine, 3,4-dihydroxyphenylethanol and 3,4-dihydroxyphenylglycol, respectively, was favored. Under these conditions, the induction of the phi-isoenzyme again produced only a small increase in the formation of the acid products, whereas the induction of the tau-isoenzyme had no effect on acid production from biogenic amine metabolism. The results suggest that neither the phi- nor the tau-forms of ALDH are involved in the hepatic metabolism of dopamine or norepinephrine and support the conclusion that the oxidation of the aldehyde derived from dopamine occurs in mitochondria [A. W. Tank, H. Weiner and J. Thurman, Biochem. Pharmac. 30, 3265 (1981)].

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Biochemical genetic variants in mice selectively bred for sensitivity or resistance to ethanol-induced sedation.

The distribution of biochemical genetic variants was examined among eight inbred strains of mice, which served as contributors to a heterogeneous stock of mice (HS), and in short-sleep (SS) and long-sleep (LS) mice, selectively bred from the HS stock for differential ethanol sensitivity. Fifteen loci for enzymes of alcohol and aldehyde metabolism, as well as 12 other biochemical loci, were investigated. Thirteen of these loci exhibited allelic variation between strains, of which six were separately fixed in the SS and LS mice. Comparisons of genetic similarity coefficients, based upon the distributions of allelic variants for the loci examined, with behavioural sensitivities (sleep-time) to an acute dose of ethanol for the inbred and selected strains of mice, indicated no correlations between these data. This suggests that this collective group of loci are not useful indicators of the genes selectively bred in the SS and LS strains, which are responsible for the differential sensitivities to acute doses of ethanol.

Alcohol Dehydrogenase↗
PubMed1986

Electrophysiological effects of monoamine-derived aldehydes on single neurons in neocortex and cerebellum in rats.

The electrophysiological effects of aldehydes derived from several monoamines were studied on single neurons in the cerebellum and neocortex of rats. The aldehydes derived from dopamine (3,4-dihydroxyphenylacetaldehyde) and serotonin (5-hydroxy-3-acetaldehyde) were prepared as stable disulfite complexes, from which free aldehydes were extracted. Serotonin and 5-hydroxy-3-acetaldehyde caused pronounced depression of firing rates both of cerebellar Purkinje neurons and neurons in prefrontal cortex. When locally applied from multibarrel micropipettes by pressure ejection, 5-hydroxy-3-acetaldehyde was twice as potent in the neocortex as in the cerebellum, and was equipotent with serotonin in both brain areas. The aldehyde of tryptamine also caused depressions of neuronal activity in cerebellum, but only at 5-fold higher doses than were effective for 5-hydroxy-3-acetaldehyde. 3,4-Dihydroxyphenylacetaldehyde was without effect in prefrontal cortex, but had mixed responses in the cerebellum. The results show that monoamine-derived aldehydes are physiologically active. It is possible that changes in the steady state level of these aldehydes caused by drugs such as ethanol and barbiturates might influence the electrophysiological properties of neurons in the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Genetic brain polypeptide variants in inbred mice and in mouse strains with high and low sensitivity to alcohol.

Twelve genetically determined brain polypeptide charge variants were identified by comparing cerebellar vermis of 7 inbred mouse strains and of mice selectively bred from 8 strains closely related to these 7 ancestral strains and one other for acute behavioral sensitivity to the sedative effects of ethanol. The selectively bred ethanol-sensitive (LS, long sleep) and insensitive (SS, short sleep) mice exhibited different allelic variants at 6 of these 12 gene loci expressed in the cerebellum. Variant polypeptide A1 (81 kdalton, pI 5.6) was shown to be associated with the membrane of synaptosomal mitochondria and to exhibit a basic variant in SS mice that is determined by a dominant allele. Other variant polypeptides showed codominant inheritance in F1 crosses. However, the phenotype of no single one of these brain polypeptides consistently correlated with the ethanol behavioral sensitivity of the 7 inbred mouse strains nor of 8 recombinant inbred (B X D, C57BL X DBA) strains. This finding supports the hypothesis that a substantial amount of inbreeding, leading to random fixation of alleles independent of selection for ethanol sensitivity, occurred during the breeding of the SS and LS mice. The present findings of a lack of a strong association between sleep time and a brain polypeptide variant do not preclude the existence of a major gene effect contributing to variation in acute sensitivity to ethanol but are consistent with reports that multiple loci are responsible for the difference in ethanol sensitivity between SS and LS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Inducible aldehyde dehydrogenases from rat liver cytosol.

Two rat hepatic cytoplasmic isozymes of aldehyde dehydrogenase, phi, induced by phenobarbital treatment, and tau, induced by TCDD treatment, have been purified from rat hepatic cytosol by ammonium sulfate fractionation, followed by ion-exchange and affinity chromatography. The specific activities of the two isozymes at pH 9.6 with propionaldehyde as substrate and NAD as cofactor were 2850 and 5250 nmol of NADH/min/mg protein for phi and tau isozymes, respectively. Estimates of molecular weights from gel filtration chromatography gave values of 118,000 Da for phi and 106,000 Da for tau. An isoelectric point for the tau enzyme of 6.5 was determined in an electrofocusing column, and approximately 7.2 for phi by immunoelectrophoresis. Both enzymes can oxidize a wide variety of aldehyde substrates, with Km values ranging from millimolar to micromolar. Long-chain aliphatic and aromatic aldehydes using NAD as cofactor tend to be the best utilized substrates. Only the tau enzyme is able to use NADP as cofactor. The measured Km for phi at pH 7.2 for acetaldehyde was 1.97 mM and for tau, 12.1 mM. Both enzymes showed similar inhibition characteristics with sodium arsenite and disulfiram, although the phi enzyme tended to be slightly more sensitive to all inhibitors.

Aldehyde Dehydrogenase↗
PubMed1985

Partial purification and properties of human brain aldehyde dehydrogenases.

Acetaldehyde and biogenic aldehydes were used as substrates to investigate the subcellular distribution of aldehyde dehydrogenase activity in autopsied human brain. With 10 microM acetaldehyde as substrate, over 50% of the total activity was found in the mitochondrial fraction and 38% was associated with the cytosol. However, with 4 microM 3,4-dihydroxyphenylacetaldehyde and 10 microM indoleacetaldehyde as substrates, 40-50% of the total activity was found in the soluble fraction, the mitochondrial fraction accounting for only 15-30% of the total activity. These data suggested the presence of distinct aldehyde dehydrogenase isozymes in the different compartments. The mitochondrial and cytosolic fractions were, therefore, subjected to salt fractionation and ion-exchange chromatography to purify further the isozymes present in both fractions. The kinetic data on the partially purified isozymes revealed the presence of a low Km isozyme in both the mitochondria and the cytosol, with Km values for acetaldehyde of 1.7 microM and 10.2 microM, respectively. However, the cytosolic isozyme exhibited lower Km values for the biogenic aldehydes. Both isozymes were activated by Mg2+ and Ca2+ in phosphate buffers (pH 7.4). Also, high Km isozymes were found in the mitochondria and in the microsomes.

Aldehyde Dehydrogenase↗
PubMed1985

Genetics of alcoholism.

Great progress has been made by research on the contribution genetic factors make to a vulnerability toward alcoholism. Animal studies have demonstrated the importance of genetics in ethanol preference and levels of consumption, and human family, twin, and adoption research have revealed a 4-fold higher risk for offspring of alcoholics, even if they were adopted out at birth. The work presented in this symposium reviews the ongoing search for genetic trait markers of a vulnerability toward alcoholism. Dr. Li has used both animal and human research to demonstrate the possible importance of the genetic control of enzymes involved in ethanol metabolism and has worked to help develop an animal model of alcoholism. The possible importance of subgroups with different levels of predisposition toward alcoholism is emphasized by Dr. Cloninger. An overview of the studies of sons of alcoholics, given by Dr. Schuckit, reveals the potential importance of a decreased intensity of reaction to ethanol as part of a predisposition toward alcoholism and discusses the possible impact of some brain waves and ethanol metabolites to an alcoholism vulnerability. Dr. Deitrich reviews interrelationships between studies of animals and humans in the search for factors involved in a genetic vulnerability toward alcoholism. Taken together, these presentations underscore the importance of genetic factors in alcoholism, review animal and human research attempting to identify markers of a vulnerability, and reveal the high level of interaction between human and animal research.

Adoption↗
PubMed1984

Blood and liver acetaldehyde concentrations during ethanol oxidation in C57 and DBA mice.

Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artefactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 mumole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 mumole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Artefactual acetaldehyde formation during the analytical procedures was obtained with the use of hemolysis, with or without thiourea, and semicarbazide methods for blood acetaldehyde determination. The magnitude of the artefactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. Earlier reported mice blood acetaldehyde concentrations are suggested to be re-evaluated.

Acetaldehyde↗
PubMed1983

Behavioral evidence for the involvement of gamma-aminobutyric acid in the actions of ethanol.

Behavioral interactions between ethanol and GABA-mimetic and GABA antagonist drugs were evaluated by duration of narcosis and motor incoordination (inhibition of bar holding) in mice. Aminooxyacetic acid (AOAA), baclofen, and tetrahydroisoxazolopyridineol (THIP) (GABA mimetics) lengthened ethanol narcosis, while picrotoxin shortened ethanol narcosis. AOAA and baclofen also enhanced the incoordinating effects of ethanol, while picrotoxin and bicuculline (GABA antagonists) had the opposite effect. In addition, the incoordinating effects of AOAA and baclofen were potentiated by low doses of ethanol, while incoordination produced by bicuculline was antagonized by ethanol. Mice selected for genetic differences in neurosensitivity to ethanol (LS and SS strains) displayed corresponding differences in the incoordinating effects of baclofen and THIP. Furthermore, chronic ingestion of ethanol resulted in a decrease in the incoordinating effect of THIP. These results, together with electrophysiological, biochemical, and behavioral data from other laboratories, suggest that: (1) augmentation of GABA effects is involved in the incoordinating and soporific actions of ethanol; (2) one factor responsible for genetic differences in ethanol response is sensitivity to GABA; and (3) ethanol tolerance and dependence may be related to decreased sensitivity to GABA.

Animals↗
PubMed1982

Neuropharmacogenetics and behavioral genetics.

Genetic studies of neurotransmitter processes to date differ from most behavioral genetic studies in that the former have rarely considered individual variability, have tended to look only for single-gene effects, and generally have overlooked or ignored environmental influences. After examining these differences, we suggest that a rapprochement between the two fields will yield synergistic benefits in studies of the genetics of neuropharmacological processes as they affect behavior.

Animals↗
PubMed1982

The in vivo metabolism of tertiary butanol by adult rats.

The metabolism of tertiary butanol has been considered to be limited to direct conjugation of the hydroxyl group. Therefore, the alcohol has been used to differentiate between the direct effects of ethanol and those caused by metabolism or metabolic products of ethanol. The in vitro oxidation of tertiary butanol has been reported, and in this report we describe the in vivo oxidation of tertiary butanol. Radiolabeled and stable isotope-labeled acetone was recovered from animals treated with corresponding labeled t-butanol. 14CO2 was also recovered from animals treated with [14C]t-butanol.

Acetone↗