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R A Deitrich

Publications and source records attributed to R A Deitrich.

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

Initiation of ethanol self-administration by the sucrose-substitution method with HAS and LAS rats.

This study was performed to examine ethanol self-administration in rats bred for different sensitivities to the sedative effects of alcohol [the Colorado High Alcohol Sensitive (HAS) and Low Alcohol Sensitive (LAS) rats]. Four rats from each replicate line of the HAS and LAS rats (n = 16) were obtained from the University of Colorado, and initiation to self-administer ethanol by the sucrose-substitution procedure was attempted. Before the initiation procedure was conducted, home-cage ethanol intake and preference ratio did not differ between LAS and HAS rats. During the initiation procedure, the LAS rats came to self-administer 10% ethanol (v/v) at similar levels as outbred Wistar rats initiated with the same procedure (approximately 0.4 g/kg/session). The HAS rats, however, failed to initiate (approximately 0.08 g/kg/ session after completing the sucrose-substitution procedure) and lever pressing was reduced even more in the HAS rats when the ethanol concentration presented was > 10% (v/v). Three of the eight HAS rats stopped lever pressing completely when the ethanol concentration was raised to 15%. After initiation, home-cage preference ratio differed significantly between the LAS and HAS rats (LAS > HAS, p < 0.03). That the LAS rats did not consume greater amounts of ethanol compared with outbred Long-Evans or Wistar rats is contrary to our hypothesis, based on recent human data suggesting that a lower sensitivity to ethanol could result in increased alcohol intake. The finding that the HAS rats could not be initiated, while selectively bred ethanol nonpreferring rats can, is also contrary to our hypothesis. Further studies related to ethanol self-administration with the HAS line could provide important information related to the genetics of alcohol nonacceptance.

Alcohol Drinking↗
PubMed1996

Effect of administered ethanol on protein kinase C in human platelets.

There are numerous reports of the effect of ethanol on protein kinase C (PKC) in animals or with in vitro systems. However, the effect of ethanol on PKC in humans has not been extensively investigated despite the large number of studies involving PKC and human platelets. In this study, we administered ethanol to human volunteers and determined the level of PKC before and after a 0.4 g/kg dose of ethanol. We studied Native Americans and Caucasians of both sexes. There was an increases in PKC activity 60 min after ethanol administration. There were no ethnic, age, nor gender differences detected, nor was there any correlation between family history of alcoholism and the basal or stimulated platelet PKC levels. Neither was there any correlation of basal or stimulated PKC activity with the genotypes for ADH2, ADH3, ALDH2, CYP2E1, and CYP1A2.

Adult↗
PubMed1996

Genetic selection and characterization of mouse lines for acute functional tolerance to ethanol.

Rapid adaptation to central nervous system inhibitory effects of ethanol is observed in animals and humans and this acute functional tolerance (AFT) is influenced by genotype in rodents. Studies have been conducted to identify neurochemical processes influencing AFT to ethanol, but little is known regarding genetic regulation of AFT or genetic influences on processes that mediate acquisition of AFT. Our study was designed to develop, by selective breeding, lines of mice that differ in acquisition of AFT to ethanol; such mouse lines will be valuable in identifying the neuroadaptive processes mediating AFT. AFT is defined as the difference in blood ethanol concentration (BEC) at regaining balance on a stationary dowel rod after two consecutive doses of ethanol, 1.75 followed by 2.0 g/kg. Starting with a genetically heterogeneous foundation stock (HS/lbg), seven generations of selective breeding has been completed for high (HAFT1), low (LAFT1), and control lines and four generations have been completed for the replicate HAFT2 and LAFT2 lines. The lines do not differ in initial sensitivity to ethanol; however, the means for AFT scores differ by 2.3- and 4.3-fold for females and males, respectively (106.5 vs. 46.5 mg ethanol/dl blood) for females and 106.2 vs. 24.8 mg/dl for males). Frequency distributions for HAFT1 and LAFT1 show only modest overlap in AFT scores. The lines differ in rates of acquisition of AFT, but not in rates of ethanol clearance. Heritabilities were 0.04 and 0.26 for HAFT1 and LAFT1 lines, respectively, indicating that the selection was asymmetrical. Evidence is provided indicating that practice during intoxication has little effect on acquisition of AFT in HAFT1 and LAFT1 lines.

Animals↗
PubMed1995

Behavioral effects and pharmacokinetics of propofol in rats selected for differential ethanol sensitivity.

High- and low-alcohol sensitivity (HAS and LAS) rats have been selected for their differences in ethanol-induced sleep time. The rats also differ in sensitivity to pentobarbital, halothane, isoflurane, and enflurane. To determine if this sensitivity extended to propofol, the anesthetic requirements were measured. In this study, the sleep time and the tissue levels of propofol at awakening, as well as the pharmacokinetics, were evaluated. Propofol was administered intravenously. For one group of rats, sleep times were measured; blood and brain samples were taken at awakening. Blood samples were collected in another group of rats at frequent intervals from 0 to 90 min after injection. Propofol concentration of the samples was determined by gas chromatography. The pharmacokinetic analysis was performed using a nonlinear least-squares regression program. Sleep time was not different; however, blood and brain propofol levels at awakening showed a small, but significant difference between HAS and LAS rats. Propofol blood concentration-time curve data were fitted to a three-compartment model. Pharmacokinetic parameters were also not different between the rat lines. However, sleep time was 50% longer in female rats than male rats in both strains (p < 0.0001). The rates of propofol clearance were slower in female rats, because of different rates of disappearance from the second compartment. The observations suggest that the genetic selection for ethanol sensitivity selection for propofol sensitivity was not nearly as intense and presumably involves some different genes. These two central nervous system depressants would seem to differ significantly in their mechanism of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1995

Chronic ethanol consumption alters effects of ethanol in vitro on brain membrane structure of high alcohol sensitivity and low alcohol sensitivity rats.

In this study, we examined if differences in initial membrane sensitivity to ethanol were associated with development of membrane tolerance to ethanol. High Alcohol Sensitivity (HAS) and Low Alcohol Sensitivity (LAS) rats were administered a 15% ethanol solution in water as the sole source of fluid for 30 days. The amount of ethanol consumed per day did not significantly differ between the HAS and LAS rats. Development of membrane tolerance to in vitro effects of ethanol has been previously reported for bulk membrane fluidity and protein-lipid interaction. Our data expands the understanding of "membrane tolerance" phenomenon to protein distribution and bilayer interdigitation. We also introduce genotype-dependent and genotype-independent properties of the membrane tolerance to ethanol. ethanol treatment produced genotype-dependent and genotype-independent membrane tolerance to ethanol. The in vitro effects of ethanol on synaptic plasma membrane (SPM) protein distribution and lipid bilayer interdigitation were abolished or decreased in the SPM of chronic ethanol-treated HAS rats, as compared with the SPM of HAS control rats (genotype-dependent tolerance). Protein distribution and bilayer interdigitation were not affected by ethanol in vitro in either chronic ethanol-treated or control LAS rats. Genotype-independent tolerance to ethanol in vitro was observed for SPM annular and bulk bilayer fluidity in chronic ethanol-treated HAS and LAS rats. It is concluded that initial sensitivity to ethanol contributes to the development of membrane tolerance to ethanol in HAS and LAS rats.

Alcoholism↗
PubMed1995

Aldehyde dehydrogenase activities in the brains of rats and mice genetically selected for different sensitivity to alcohol.

Aldehyde dehydrogenase activity in brain has been studied for many years. However, the question of its role in the actions of ethanol in the brain has not been resolved. We have utilized mice and rats selectively bred for sensitivity or resistance to the initial hypnotic effects of ethanol to gain some insight into the possible involvement of brain aldehyde dehydrogenase in the actions of ethanol. We compared the levels of aldehyde dehydrogenase activity in the brains of these selected lines of rodents by histochemical methods. It was found that, although aldehyde dehydrogenase activity was detected in many areas of the brain, only in the cerebellar Purkinje cells was there a difference between sensitive and resistant lines of mice or rats. The resistant lines (Short Sleep mice and Low Alcohol Sensitive rats) had statistically higher levels of aldehyde dehydrogenase than did the sensitive lines (Long Sleep mice and High Alcohol Sensitive rats). Although this does not prove that aldehyde dehydrogenase or aldehydes are involved in the central actions of ethanol, it provides another piece of evidence in this direction.

Alcoholic Intoxication↗
PubMed1994

Effect of pentobarbital and gaseous anesthetics on rats selectively bred for ethanol sensitivity.

Rats have been genetically selected to have a differential hypnotic response to an acute injection of ethanol. These high alcohol sensitive (HAS) and low alcohol sensitive (LAS) rats were used to investigate commonalities of the mechanism of action of several gaseous anesthetics, pentobarbital and ethanol. Similar studies have been carried out extensively with mouse lines also differentially sensitive to ethanol (short- and long-sleep mice). Like the mice, the rats are also differentially sensitive to the two gaseous anesthetics, enflurane and isoflurane. However, in contrast to results with these mice, we find that the HAS and LAS rats are differentially sensitive to halothane and pentobarbital in the same direction as their sensitivity to ethanol. In other studies, the rats also have been found to be differentially sensitive to phenobarbital as are SS and LS mice. These results show that, by the use of these anesthetics in combination with selectively bred rodent lines, many new opportunities for dissecting the molecular mechanisms of anesthetic agents present themselves.

Anesthetics↗
PubMed1993

Selective breeding for initial sensitivity to ethanol.

Selective breeding for initial sensitivity to ethanol has been carried out by a number of investigators in order to investigate the mechanisms by which ethanol brings about a myriad of effects on the mammalian central nervous system. In addition the availability of these selectively bred animals provides clues to the causes of the genetic predisposition of humans to alcoholism. Eventually it is envisioned that the synteny between the mouse and human genomes will allow identification of specific genes responsible for acute effects of ethanol in both species as well as clues as to how alcoholism in humans can be better identified, prevented, and treated.

Alcohol Drinking↗
PubMed1993

Phosphorylation of cytochrome P4502E1 (CYP2E1) by calmodulin dependent protein kinase, protein kinase C and cAMP dependent protein kinase.

Phosphorylation of pure cytochrome P4502E1 (CYP2E1) was achieved in vitro using Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), protein kinase C (PKC) and cAMP-dependent protein kinase (PKA). The stoichiometry and time-course of phosphorylation were determined. CaM kinase II was the most efficient enzyme capable of catalyzing this phosphorylation reaction: the maximum incorporation of 32PO4 was 0.8 mol/mol CYP2E1 in 20 min. PKA phosphorylated a maximum of 0.7 mol of 32PO4/mol of cytochrome within 60 min. The phosphorylation by PKC reached a maximum of 0.19 mol of 32PO4/mol of cytochrome and this occurred within a few minutes of incubation. Limited digestion by S. aureus V8 protease (SAP) of CYP2E1, which had been phosphorylated by either PKA and PKC, yielded a single major phosphopeptide with an M(r) of approximately 18,000. Limited digestion of CYP2E1, that had been phosphorylated by CaM kinase II, yielded phosphorylated polypeptides with M(r) of approximately 18,000 and 15,000. These results raise the possibility that these three kinases may be involved in the regulation of CYP2E1.

Animals↗
PubMed1992

Selective breeding of rats differing in sensitivity to the effects of acute ethanol administration.

Selective breeding of rats for sensitivity to the anesthetic effects of ethanol is being carried out with rats derived from the genetically heterogeneous N/Nih stock. Thirteen generations of within family selection have been achieved with replicate high (HAS), low (LAS) and control alcohol sensitive (CAS) lines. Significant separation between lines on sleep time and blood ethanol concentration (BEC) at awakening following ethanol administration has been achieved. In general, the results obtained so far replicate the findings with short (SS) and long (LS) sleep mice. One exception is that the high alcohol sensitivity rats (HAS) also appear more sensitive to pentobarbital relative to LAS rats. This finding is opposite to that which occurs with SS and LS mice where the low ethanol sensitive SS mice appear more sensitive to pentobarbital than the LS mice.

Alcoholic Intoxication↗
PubMed1992

Surface exposure of synaptosomal gangliosides from long-sleep and short-sleep mice.

A galactose oxidase/NaB[3H]4 technique was used to examine the relative surface exposure of gangliosides from whole brain synaptosomes of long-sleep (LS) and short-sleep (SS) mice. The surface exposure of the monosialoganglioside, GM1, did not differ between the two lines. Surface exposure of the polysialogangliosides GD1a, GD1b, and GT1b, however, was significantly greater in LS synaptosomes than in SS. Hydrolysis of the polysialogangliosides by neuraminidase to the end-product, GM1, at early time periods occurred more rapidly in LS than in SS synaptosomes. Upon exposure to either 250 mM or 50 mM ethanol, LS synaptosomal ganglioside surface exposure was decreased, but that of SS was increased. Pairwise comparisons of the individual ganglioside classes indicated that the decrease in LS synaptosomal ganglioside surface exposure was attributable to decreases in the polysialogangliosides, compared with controls. The ethanol-induced increase in SS synaptosomal ganglioside surface exposure, however, was mainly due to an increased surface exposure of only GD1a. These results suggest that intrinsic differences in the surface exposure of gangliosides and/or the magnitude and direction of ethanol-induced changes in ganglioside surface distribution may reflect biophysical or modulatory mechanisms by which this class of compounds modifies membrane sensitivity to ethanol. These results suggest that further studies should be performed to determine whether gangliosides are factors in genetically determined sensitivity to ethanol.

Alcoholic Intoxication↗
PubMed1992

Enzymatic production of acetaldehyde from ethanol in rat brain tissue.

The capacity for the brain to produce acetaldehyde (AcHO) from ethanol was determined in rat brain homogenates. Rat brains were perfused with saline-heparin solution and homogenized in a phosphate buffer. Varying amounts of tissue were incubated with ethanol (0-100 mM) for periods of up to 60 min. The reaction was stopped by the addition of desferrioxamine and ice-cold perchloric acid. Supernatants were treated with dinitrophenylhydrazine reagent, extracted with isooctane in the presence of an internal standard, and the derivatives were separated by HPLC. The addition of 4-methyl pyrazole (an alcohol dehydrogenase inhibitor) or metyrapone (a cytochrome P450 inhibitor) had no effect on the amount of recovered AcHO. On the other hand, treatment with the catalase inhibitors sodium azide, cyanamide, or 3-amino-1,2,4-triazole blocked the production of AcHO while the addition of exogenous peroxide or a peroxide-generating system enhanced the production of AcHO. Overall, these results suggest that AcHO may be produced in the brain during alcohol intoxication, through the action of the enzyme catalase.

Acetaldehyde↗
PubMed1992

Differences in hepatic microsomal cytochrome P-450 isoenzyme induction by pyrazole, chronic ethanol, 3-methylcholanthrene, and phenobarbital in high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats.

High and low alcohol sensitivity (HAS and LAS) rats have been selected for their differences in ethanol-induced sleep time. Liver monooxygenase activities were studied in HAS and LAS rats before and after treatments with known inducers such as chronic ethanol, pyrazole, 3-methylcholanthrene (3-MC) and phenobarbital (PB) to determine whether the selection procedure also selected for differences in the cytochrome P-450 (P-450) inducibility. This previously has been shown with long sleep (LS) and short sleep (SS) mice, which were selected using a similar criterion. 3-MC and PB, in conjunction with chronic ethanol treatment, were used in order to evaluate the interactions of ethanol with these inducers. Prior to treatment, total P-450 content was slightly lower in LAS than in HAS rats. However, both lines displayed the same microsomal monooxygenase activities related to different P-450 isozymes. This was demonstrated by ethoxyresorufin deethylation (EROD) for cytochrome P-450 1A1 (CYP1A1), acetanilide hydroxylation (ACET) for CYP1A2, pentoxyresorufin dealkylation (PROD) for CYP2B, 1-butanol oxidation (BUTAN) and N-nitrosodimethylamine demethylation (NDMA) for CYP2E1. After the different treatments, HAS rats did not differ from LAS rats in their CYP2E1 inducibility. However, pyrazole, PB and 3-MC treatment led to differences in CYP1A and CYP2B monooxygenase activities between the two lines. The enhancement of PROD by pyrazole treatment was less prominent in LAS (1.7-fold of the control value) than in HAS rats (3.8-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1991

The cDNA sequence and chromosomal location of the murine GABAA alpha 1 receptor gene.

The murine GABAA/benzodiazepine (GABAA/BZ) receptor alpha 1 subunit cDNA has been isolated from a BALB/c mouse brain library and sequenced. The cDNA is 2665 nucleotides long with an open reading frame of 455 amino acids. It shows significant homology to the GABAA receptor alpha 1 subunit cDNA sequences of other species. Excluding deletions, the murine GABAA alpha 1 receptor exhibits 96% nucleotide and 100% amino acid sequence homology to the rat alpha 1 receptor cDNA and over 91% nucleotide and 98% amino acid sequence homology to the bovine and human alpha 1 receptor cDNAs in the protein coding region. This murine cDNA was used to locate the alpha 1 receptor subunit gene, Gabra-1, to murine Chromosome 11 between Il-3 and Rel. This assignment extends proximally the segment of mouse Chromosome 11 with known homology to human chromosome 5.

Amino Acid Sequence↗
PubMed1991

Responses to cholinergic agonists of rats selectively bred for differential sensitivity to ethanol.

Alcoholics are almost invariably heavy users of tobacco. Both alcoholism and smoking appear to be influenced by genetic factors but it is not known whether the same or different genes regulate the abuse of ethanol and nicotine. Recent studies have demonstrated that the long-sleep (LS) and short-sleep (SS) mouse lines, which were selectively bred for differences in ethanol-induced anesthesia ("sleep-time"), also differ in several effects of nicotine and the muscarinic agonist, oxotremorine. In order to determine whether or not these differences are due to chance, the relative sensitivities of rat lines which were selectively bred for differences in ethanol-induced sleep-time were determined. The high alcohol sensitivity (HAS) rat line was more sensitive to the locomotor and body temperature depressant effects of nicotine than was the low alcohol sensitivity (LAS) rat line. The control line (CAS) was intermediate in sensitivity. The rat lines did not differ in sensitivity to oxotremorine's hypothermia-producing effects. The numbers and affinities of two classes of brain nicotinic receptors were measured in eight brain regions. No differences among the rat lines were detected. These results suggest that ethanol elicits some of its depressant actions via an effect on brain nicotinic systems, but the differences in sensitivity to ethanol and nicotine are probably not due to differences in the number of brain nicotinic receptors. Perhaps this interaction explains the high correlation between alcoholism and smoking in humans.

Animals↗