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Biomedical subjects

R A Deitrich

Publications and source records attributed to R A Deitrich.

At least 19 recordsLinked to original sources
PubMed1998

Acute tolerance to the ataxic effects of ethanol in short-sleep (SS) and long-sleep (LS) mice.

The objective of this series of studies was to examine the relationship between alcohol sensitivity and the development of very rapid acute tolerance to alcohol in mice. In order to measure acute tolerance to alcohol, a behavioral test was developed using a rotorod. In the first study, mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute hypnotic effects of ethanol were used, as well as mice from the base population (heterogeneous stock, HS). Mice were trained to run on the rotorod at a speed of 14 rpm to a criterion of 200 s, in four daily training sessions. On the test day, baseline measurements of rotorod performance were taken and mice were injected i.p. with alcohol in doses from 0 to 2.5 g/kg. Animals were tested at 1-min intervals for the first 5 min following injection, then at 5-min intervals for a total of 30 min. The results demonstrated that SS and HS mice developed tolerance within 10 min following the alcohol injections. LS mice did develop some acute tolerance, but at a much slower rate than the SS or HS mice. In the second study, the effects of intoxicated practice on the rates of acute tolerance development were examined in the SS, HS and LS mice at a dose of 2.0 g/kg alcohol. A total of ten groups of each strain were given a different number of practice trials (ranging from one to ten) on the rotorod prior to a final test session at 30 min post-injection. The results provide evidence that SS and HS mice are capable of developing acute tolerance independent of practice. That is, the group of animals injected at 0 time and tested ten times up to 30 min were no better at the 30-min time point than the group injected at 0 time and tested only once at 30 min. On the other hand, the LS mice showed a modest practice effect, developing additional tolerance to the ataxic effects of alcohol with increasing intoxicated practice. Overall, these studies demonstrated that mice can develop acute tolerance within minutes following alcohol exposure, and that this ability is correlated with the initial sensitivity to alcohol.

Alcoholic Intoxication↗
PubMed1998

Role of GABA in the actions of ethanol in rats selectively bred for ethanol sensitivity.

Rats from the N/Nih heterogeneous stock have been selectively bred for high (HAS) or low (LAS) initial sensitivity to injected ethanol as measured by duration of the loss of the righting reflex. The selection for ethanol sensitivity in these lines apparently has reached a maximum. These lines are useful to elucidate the central nervous system mechanisms of the genetic differences between the lines and also provide clues to the mechanisms of ethanol's action. We have found that: 1) ethanol, etomidate, and ketamine but not propofol produce different sleep times and brain levels of the drug on awakening between these two lines; 2) only ethanol, etomidate, and ketamine produced significant differences between the HAS and LAS rats in GABA-mediated stimulation of chloride uptake into brain microsacs; 3) GABA, propofol, and etomidate decreased the Kd for flunitrazepam binding to whole-brain membranes but equally in both lines. Neither ethanol nor ketamine had an effect; 4) only GABA, ethanol, and etomidate increased the Kd for TBPS binding and only GABA decreased Bmax of TBPS binding. As with the previous selection for ethanol sensitivity in mice (short and long sleep) these lines of rats have very marked line differences in GABA-mediated events, and these are correlated with the sedative effects of ethanol. From these and previous studies we know that the major differences between selected lines of mice and rats are that the mouse lines are not differentially sensitive to halothane or pentobarbital while the rat lines are. However, the mouse lines are differentially sensitive to propofol and the rat lines are not. These data should be useful in dissecting the actions of ethanol at the GABA(A) receptor.

Alcoholic Intoxication↗
PubMed1997

Phenobarbital sensitivity in HAS and LAS rats before and after chronic administration of ethanol.

Rats selectively bred for high alcohol sensitivity (HAS) or low alcohol sensitivity (LAS) were tested for initial sensitivity to hypnotic doses of ethanol and a locomotor-altering dose of phenobarbital. Following 6 weeks of either a pair-fed control or 33% ethanol-derived calorie diet, animals were tested again for tolerance to ethanol and cross-tolerance to phenobarbital. HAS and LAS rats did not differ in baseline open field or Rotarod activity before chronic ethanol treatment. However, HAS rats were more sensitive to 50 mg/ kg phenobarbital relative to LAS rats. Both control- and ethanol-diet rats appeared to be less sensitive to phenobarbital after the 6-week treatment period. Chronic ethanol-exposed HAS and LAS rats demonstrated tolerance to ethanol and cross-tolerance to phenobarbital, and in particular LAS rats were even more active in the open field following phenobarbital relative to controls. In summary, significant differences in response to phenobarbital were observed between HAS and LAS rats. These observations suggest that initial sensitivity and tolerance to ethanol are associated with differences in phenobarbital sensitivity and are influenced by similar genes.

Animals↗
PubMed1997

A description of alcohol/drug use and family history of alcoholism among urban American Indians.

The patterns of alcohol consumption, family history of alcoholism, and lifetime and current diagnoses of substance dependence were determined in a sample of American Indians (n = 105) living in Denver. Subjects were recruited through flyers, posters, and advertisements placed in local newspapers, the Denver Indian Center, and Denver Indian Health and Family Services. Subjects were interviewed regarding their education, employment, past and present drug and alcohol use (including frequency/quantity, beverage type, and pattern of intake) and family history of alcoholism. The drug and alcohol sections of the Diagnostic Interview Schedule were administered in order to determine lifetime and current prevalence of substance dependence. Although there are limits to the generalizability of these data due to the use of a non-random sampling method, the results indicate that approximately half of the sample (50.5%) were abstinent or irregular drinkers with moderate intake (3.3 drinks/occasion). Binge drinkers (3.8%) consumed large amounts of alcohol per occasion, with a mean of 21.6 drinks. Also, 45.5% of the sample were regular drinkers (at least once/wk) with a mean of 11 standard drinks/occasion. The rate of current alcohol dependence (33.3%) and other drug dependence (18.1%) was relatively high with cocaine and cannabis the primary drugs of abuse. The most striking aspect of the sample was the very high rate of family history of alcoholism (60.6% with at least one alcoholic parent) and only 11.1% with no primary or secondary alcoholic family members.

Adult↗
PubMed1997

Effect of exogenous GM1 on ethanol sensitivity in selectively bred mouse lines.

Ethanol sensitive long-sleep (LS) and ethanol resistant short-sleep (SS) mice are lines that have been genetically selected for differential central nervous system sensitivities to the hypnotic effect of ethanol. Because they were genetically selected only for differences in sensitivity to ethanol hypnosis, biochemical and physiological differences between them are likely related to their differential ethanol sensitivity. The synaptosomal and whole brain concentration of GM1 ganglioside was previously shown to differ significantly between the lines. Further, GM1 alters membrane responses to ethanol, including a differential effect on LS and SS synaptosomal membrane disordering. Therefore, GM1 was administered intracerebroventricularly (i.c.v.) with micro-osmotic pumps, to partially bypass the blood-brain barrier and to test its effect on CNS sensitivity to ethanol hypnosis in LS and SS mice. In the first experiment, 3 days' infusion of GM1 (20 micrograms/microliters, 24 microliters/day), saline control and treated LS and SS mice were tested for both regaining of the righting reflex and waking brain ethanol concentration. Incorporation of 3H-GM1 into brain membranes was verified by scintillation spectroscopy. GM1 did not alter ethanol sensitivity or brain ethanol concentration at time of waking in LS mice. Conversely, SS mice treated with GM1 were significantly more sensitive to ethanol hypnosis than saline controls as measured by the time to regain the righting reflex ("sleep time") and waking brain ethanol concentrations. In the second experiment, GM1-treated SS mice were again significantly more sensitive to ethanol hypnosis than saline controls. GM1 incorporation into the contralateral and ipsilateral cerebral hemispheres was determined by high-performance liquid chromatography.

Animals↗
PubMed1996

Neurotensin levels and receptors in HAS and LAS rat brains: effects of ethanol.

Previous studies of neurotensin (NT) levels and NT receptor densities in specific brain regions of mice selectively bred for differences in sensitivity to ethanol have shown that NTergic processes may mediate some actions of ethanol. In the present study, we have determined the levels of NT and NT receptor densities in specific brain regions of HAS and LAS rats that have been selectively bred for differences in sensitivity to ethanol-induced loss of righting response. Regional differences in NT levels were observed in brains from both HAS and LAS rats and values in hypothalamus, ventral midbrain, and nucleus accumbens from female rats were 25 to 75% higher than levels in corresponding regions from male rats. However, there were no significant line differences in NT-ir levels in corresponding regions from HAS and LAS animals. High-affinity binding (NTH Bmax values), measured by Scatchard analyses, were higher in ventral midbrain from HAS males than from LAS males. NTH receptor densities were higher in HAS males than in HAS females; sex differences were not observed in the LAS line. There were no significant line or sex differences between HAS and LAS in low-affinity (NTL) Bmax values in any brain region. In HAS females, subhypnotic doses of ethanol produced a decrease in NT levels in nucleus accumbens, whereas, hypnotic doses caused an increase in NT levels. Likewise, hypnotic doses elicited increases in NT levels in hypothalamus of female HAS and LAS, but not in ventral midbrain or caudate putamen. These results are consistent with low dose activation of mesolimbic and nigrostriatal dopaminergic neurons in which NT is colocalized with dopamine and with high dose inhibition of these pathways.

Animals↗
PubMed1996

Actions of long chain alcohols on GABAA and glutamate receptors: relation to in vivo effects.

1. The effects of n-alcohols on GABAA and glutamate receptor systems were examined, and in vitro effectiveness was compared with in vivo effects in mice and tadpoles. We expressed GABAA, NMDA, AMPA, or kainate receptors in Xenopus oocytes and examined the actions of n-alcohols on receptor function using two-electrode voltage clamp recording. 2. The function of GABAA receptors composed of alpha 1 beta 1 or alpha 1 beta 1 gamma 2L subunits was potentiated by all of the n-alcohols studied (butanol-dodecanol). 3. In contrast to GABAA receptors, glutamate receptors expressed from mouse cortical mRNA or from cRNAs encoding AMPA (GluR3)- or kainate (GluR6)-selective subunits were much less sensitive to longer chain alcohols. In general, octanol and decanol were either without effect or high concentrations were required to produce inhibition. 4. In contrast to the lack of behavioural effects by long chain alcohols reported previously, decanol produced loss of righting reflex in short- and long-sleep mice, indicating that the in vivo effects of decanol may be due in part to actions at GABAA receptors. Furthermore, butanol, hexanol, octanol, and decanol produce similar potentiation of GABAA receptor function at concentrations required to cause loss of righting reflex in tadpoles, an in vivo model where alcohol distribution is not a compromising factor. 5. Thus, the in vivo effects of long chain alcohols are not likely to be due to their actions on NMDA, AMPA, or kainate receptors, but may be due instead to potentiation of GABAA receptor function.

Alcohols↗
PubMed1996

Voluntary alcohol consumption in BXD recombinant inbred mice: relationship to alcohol metabolism.

Studies were initiated to characterize behaviorally and biochemically C57BL/6J and DBA/2J inbred mice, as well as BXD Recombinant Inbred (RI) strains derived from them. The C57BL/6J, DBA/2J, and 7 BXD RI strains were tested for voluntary alcohol consumption (VAC) by receiving 4 days of forced exposure to a 10% (w/v) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. Measures of VAC included the absolute intake of alcohol (g/kg), as well as alcohol preference. A wide range of VAC was displayed by the various BXD RI strains with a continuous (rather than bimodal) distribution, indicating that there is likely to be additive effects of several genes involved in regulating alcohol-related behaviors. Kinetic characteristics of aldehyde dehydrogenase and catalase in liver and brain of the C57BL/6J, DBA/2J, and BXD strains of mice were determined to test the hypothesis that the genetic regulation of the levels of alcohol-metabolizing enzymes mediate differences in VAC. Aldehyde dehydrogenase activity was determined spectrophotometrically by observing the change in absorption at 340 nm. Catalase activity was determined by measuring oxygen production with a Yellow Springs Biological Oxygen monitor and oxygen electrode. There was a strong negative relationship between VAC and brain catalase activity in the BXD RI and parental strains. These data suggest that RI strains are likely to be useful genetic models in the examination of quantitative trait loci controlling VAC and other responses to alcohol.

Alcohol Drinking↗
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↗