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Biomedical subjects

E J Gallaher

Publications and source records attributed to E J Gallaher.

At least 19 recordsLinked to original sources
PubMed1994

Amelioration of lactic acidosis with dichloroacetate during liver transplantation in humans.

BACKGROUND: Marked lactic acidosis occurs during orthotopic liver transplantation (OLT), especially during the anhepatic phase. Current standard therapy is NaHCO3, although it may exacerbate intracellular acidosis, increase plasma lactate, and contribute to hypernatremia. Alternatively, dichloroacetate (DCA) stimulates pyruvate oxidation in vivo, reduces plasma lactate, and moderates intracellular acidosis. The aims of this study were to test the efficacy of DCA to control lactic acidosis, reduce the NaHCO3 requirement and incidence of hypernatremia, and stabilize perioperative acid-base homeostasis. Others aims were to examine the DCA pharmacokinetic profile during OLT and the role of lactate metabolism in OLT-associated hyperglycemia. METHODS: Patients (n = 66) for OLT were divided into two equal groups to receive or not receive DCA during OLT. DCA 40 mg.kg-1 was infused over 60 min after induction of anesthesia and 4 h later. Plasma DCA concentration was measured by gas chromatography-mass spectroscopy, and pharmacokinetics were assessed by a one-compartment model. Serial arterial blood gases, lactate, Na+, glucose, and hemodynamic measurements were compared, as were intraoperative utilization of blood products, CaCl2, and NaHCO3. RESULTS: Plasma DCA concentration was maintained between 0.28 and 1.18 mM during OLT, with peak concentrations of 0.73 +/- 0.06 (mean +/- SE) and 1.18 +/- 0.09 mM, respectively after the first and second doses. In control patients, plasma lactate was 1.07 +/- 0.04 at baseline and 1.20 +/- 0.06 before incision and reached a peak of 7.30 +/- 0.41 mM after graft reperfusion. In DCA-treated patients, the respective values were 1.07 +/- 0.06 (difference not significant), 0.63 +/- 0.05 (P < 0.001), and 3.39 +/- 0.20 (P < 0.001) mM. Intraoperative changes in arterial blood pH, HCO3(-1), and base excess were comparable though less marked in DCA-treated patients, whose NaHCO3 requirement was reduced (0.59 +/- 0.36 vs. 2.83 +/- 0.53 mEq.kg-1 in control patients, P < 0.001). There was no difference between groups in requirements for CaCl2 or blood products, in intraoperative hemodynamics, in duration of the surgical stages, or in graft ischemia times. Twelve control and 4 DCA-treated patients exhibited a plasma Na+ concentration > 145 mEq/1 at completion of surgery (P < 0.05). Hyperglycemia was not attenuated by DCA despite decreased plasma lactate concentration. Sixteen and 28 h after graft reperfusion, when plasma DCA had been eliminated, plasma lactate and degree of metabolic alkalosis did not differ between groups. CONCLUSIONS: DCA safely and effectively attenuated lactic acid accumulation and moderated acidosis during OLT. DCA decreased the requirement for NaHCO3 therapy and the incidence of hypernatremia. OLT-associated hyperglycemia did not result from lactate-induced stimulation of hepatic gluconeogenesis. Postoperative metabolic alkalosis was not substantially influenced by lactate metabolism.

Acidosis, Lactic↗
PubMed1994

Halothane sensitivity in replicate mouse lines selected for diazepam sensitivity or resistance.

We have previously shown that mice selected for sensitivity to diazepam are also more sensitive to halothane, and that halothane augments the gamma-aminobutyric acid (GABA)-mediated chloride flux response in brain tissue from diazepam-sensitive (DS) mice to a greater degree than in diazepam-resistant (DR) mice. These findings suggest that the GABAA receptor is an important site of halothane action. To confirm this correlation, halothane requirement was determined in two independently developed replicate lines of DS and DR mice. Association of the traits of diazepam and halothane sensitivity in replicate lines of DS mice diminishes the probability that the original finding was due to a false-positive correlation, and instead suggests that it results from the common action of genes controlling diazepam sensitivity. Halothane median effective concentration (EC50) was determined by using the end-point of loss of righting reflex in two replicate lines of mice selected for diazepam sensitivity (resistant mice = diazepam high performance-1 and -2 [DHP-1 and DHP-2], sensitive mice = diazepam low performance-1 and -2 [DLP-1 and DLP-2]). DLP-1 and DLP-2 mice were sensitive to halothane, whereas DHP-1 and DHP-2 mice were resistant to halothane. Halothane EC50 in the DLP-1 and DHP-1 mice was 0.86 +/- 0.01 (SE) and 1.10 +/- 0.04 atm%, respectively (P < 0.0001), and that in the DLP-2 and DHP-2 mice was 0.88 +/- 0.01 and 0.97 +/- 0.02 atm%, respectively (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Halothane's effects on GABA-gated chloride flux in mice selectively bred for sensitivity or resistance to diazepam.

The DS (diazepam-sensitive) and DR (diazepam-resistant) lines of mice, selected on the basis of their ataxic response to diazepam, also diverge in the physiologic response of their brain gamma-aminobutyric acidA (GABAA) receptors to benzodiazepines, as indicated by augmentation of GABA-mediated chloride flux. Cross-sensitivity and -resistance to other sedatives known to interact with the GABAA-receptor have also been demonstrated in DS and DR mice. Based on the finding that these mice also show cross-sensitivity and -resistance to obtundation by halothane, we predicted that their GABAA-receptors would also exhibit a differential response to halothane as assayed by an in vitro 36Cl- influx assay using purified brain microvesicles. Consistent with this prediction, therapeutic concentrations of halothane enhanced 1 mumol/l GABA-gated flux with significantly greater potency in DS than in DR mice (halothane EC50 336 +/- 64 mumol/l (S.E.M.) vs. 605 +/- 110 mumol/l, respectively, P = 0.03), but there was no difference in maximal flux enhancement between the two lines (DS 4.7 +/- 0.4 nmol.mg-1 x 3 s-1, vs. DR 4.7 +/- 0.5 nmol.mg-1 x 3 s-1). Halothane (500 mumol/l) also shifted the entire GABA concentration-flux relationship significantly to the left, decreasing the EC50 for GABA in both the DS and DR lines. Importantly, the shift in the GABA concentration-flux response in the presence of halothane was more pronounced in the DS mice (GABA EC50 1.8 +/- 0.4 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane) than in the DR mice (GABA EC50 4.7 +/- 0.6 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Dissociation of the effect of aminoglutethimide on corticosterone biosynthesis from ataxic and hypothermic effects in DBA and C57 mice.

Adrenalectomy is frequently used to deplete adrenocortical hormones in physiological and receptor-binding studies in animals. However, this procedure is irreversible, removes both the cortex and medulla, and produces many negative side effects such as hypotension and hypoglycemia. Aminoglutethimide is a steroid synthesis inhibitor which depletes adrenocortical hormones without these negative effects. However, aminoglutethimide itself has been shown to produce behavioral and physiological deficits. In the present experiments, dose-response relationships were determined for the effects of aminoglutethimide on corticosterone levels, motor coordination, and body temperature in C57 and DBA mice. Aminoglutethimide (5.4-54 mg/kg) inhibited the increase in plasma corticosterone concentrations normally observed in response to restraint stress. Only at higher doses (170-1,000 mg/kg) were rotarod performance and body temperature affected. The corticosterone response to restraint stress recovered fully between 12 and 24 h after aminoglutethimide. In the present study, doses of aminoglutethimide were found that temporarily inhibit stressed corticosterone release without producing motor deficits and temperature decreases. These results indicate that aminoglutethimide is a potential substitute for adrenalectomy in studies on the effects of removal of adrenocortical hormones.

Adrenalectomy↗
PubMed1993

Volatile anesthetic requirements differ in mice selectively bred for sensitivity or resistance to diazepam: implications for the site of anesthesia.

One approach to elucidating the general anesthetic target has used genetic selection procedures, wherein animals are bred for sensitivity or resistance to general anesthetics and correlations are sought with a specific neuronal structural or functional defect. For example, murine strains have been developed that are either sensitive or resistant to the obtunding effects of diazepam, as assessed by their ability to maintain balance on a rotating rod. The present study explored whether diazepam-sensitive (DS) and diazepam-resistant (DR) mice might also be similarly divergent in the obtunding response to general anesthetics, by testing the requirements for halothane and enflurane in these strains. Using a carousel enclosed in a chamber, the end-point of loss-of-righting reflex was defined. For both anesthetics, the DS groups had a lower median effective dose (ED50, %atm) than did the DR group, and the reductions paralleled diazepam susceptibility. For example, with halothane, the ED50 for the DS group was 0.72 +/- 0.022 (SE); the ED50 for the DR group was 0.87 +/- 0.030 (P < 0.0001). Similar results were obtained with enflurane. Such findings associate an inbred difference in response to diazepam with altered volatile anesthetic requirement, suggesting that these two phenotypes are mediated by a common underlying mechanism.

Anesthesia, Inhalation↗
PubMed1992

Locomotor responses to benzodiazepines, barbiturates and ethanol in diazepam-sensitive (DS) and -resistant (DR) mice.

Diazepam-sensitive (DS) and -resistant (DR) mice were selectively bred for increased and reduced sensitivity to the ataxic effects of diazepam (40 mg/kg). Other response differences between DS and DR mice may reflect pleiotropic effects of the genes fixed during their selection. These mice were tested for their sensitivity to the locomotor stimulant effects of several doses of diazepam, flunitrazepam, pentobarbital, phenobarbital, and ethanol. DR mice were more sensitive than DS mice to the locomotor stimulant effects of all drugs except phenobarbital. These results largely support the hypothesis that a common biological mechanism mediates sensitivity to the stimulant effects of sedative-hypnotic drugs. Receptor mediation of the benzodiazepine effects was examined by administering the benzodiazepine receptor antagonist, RO15-1788. Locomotor depression produced by diazepam and flunitrazepam in DS mice was blocked by RO15-1788. However, while the locomotor stimulation produced by diazepam in DR mice was antagonized, the stimulant effect of flunitrazepam was not. This suggests that binding of flunitrazepam to the GABAA-benzodiazepine receptor is not necessary for production of locomotor stimulation.

Analysis of Variance↗
PubMed1991

Behavioral and neurochemical studies in diazepam-sensitive and -resistant mice.

Benzodiazepine (BZ) effects include anxiolyis, sedation, seizure protection, and muscle relaxation; the mechanisms underlying these various effects are not understood. We have recently used the rotarod test in conjunction with selective breeding techniques to develop lines of mice which are diazepam-sensitive (DS) and diazepam-resistant (DR). We review the general methods of selective breeding, along with a description of the DS/DR selection study, and then describe a variety of behavioral and neurochemical studies which have been conducted in an attempt to characterize these mice. We have investigated the effects of other sedative drugs believed to interact with the BZ receptor, including ethanol, pentobarbital, and phenobarbital. We have also tested these mice for seizure threshold and open-field activity. DS and DR mice do not differ in diazepam-induced seizure protection, suggesting that different mechanisms underlie rotarod performance and the anti-convulsant effect. These results provide evidence to support the search for nonsedating anti-convulsants. To determine the neurochemical basis for observed differences, BZ receptor density and chloride flux have been measured. We discuss the interaction between behavioral and neurochemical approaches, and describe a conceptual framework to guide future studies with these unique new animals.

Animals↗
PubMed1988

Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex.

The gamma-aminobutyric acid (GABA) receptor-operated chloride channel complex was evaluated in mice selected for differential sensitivity to the ataxic effects of diazepam (diazepam-sensitive (DS) and diazepam-resistant (DR) lines). The ataxic effects of several drugs purported to produce some of their actions through the benzodiazepine-GABA receptor complex were examined using the rotarod test. The duration of impairment produced by diazepam, ethanol, 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol (THIP) and phenobarbital was greater in the diazepam-sensitive than in the diazepam-resistant mice. In contrast, pentobarbital produced an equivalent duration of ataxia in the two lines. Muscimol-stimulated 36Cl- influx and the binding of [35S]t-butylbicyclophosphorothionate (TBPS) and [3H]flunitrazepam were measured using isolated brain membrane vesicles (microsacs). Depolarization-dependent 45Ca2+ uptake was measured in whole brain synaptosomes. Muscimol was a more potent stimulator of 36Cl- flux in the DS compared to the DR mice, although no difference between the lines was found in muscimol-stimulation of [3H]flunitrazepam binding. Flunitrazepam augmented the muscimol-stimulated 36Cl- uptake in the DS but not in the DR mice. However, no differences between the lines of mice were found in either density or affinity of [3H]flunitrazepam binding sites. Similarly, no differences in either the density or affinity of [35S]TBPS binding sites was found. Ethanol (10-45 mM) potentiated the muscimol-stimulation of 36Cl- in DS, with no effect in DR mice. However, ethanol inhibition of [35S]TBPS binding was equivalent in the two lines of mice. Pentobarbital produced an equal potentiation of the muscimol-stimulated 36Cl- flux in the two lines, but phenobarbital potentiated the muscimol-induced 36Cl- influx slightly more in DS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Initial sensitivity and tolerance to ethanol in mice genetically selected for diazepam sensitivity.

The benzodiazepine (BZ) receptor is coupled with a GABA-receptor chloride-ionophore complex. The BZs augment the GABA-induced increase in chloride conductance, which leads to postsynaptic inhibition. This effect is believed to be responsible for antianxiety, sedative, muscle relaxant, and anticonvulsant effects, but the mechanisms underlying these behavioral effects are poorly understood. Various other sedative-hypnotics, including ethanol and barbiturates, interact with this system, probably contributing to their behavioral effects. We have recently conducted a selective breeding program to develop lines of mice which are diazepam-resistant (DR) and sensitive (DS) (Gallaher EJ, Hollister LE, Gionet SE, Crabbe JC. Psychopharmacology, 93:25-30, 1987); when tested for the duration of rotarod impairment after 20 mg/kg diazepam the DR line was impaired for 71 +/- 13 min compared with 200 +/- 18 min in the DS line. In the current study we tested mice from the DR and DS lines to determine if BZ sensitivity generalized to ethanol. DS mice became ataxic with lower brain ethanol concentrations, and recovered at later times and with lower blood ethanol concentrations, than did DR mice, indicating that sensitivity differences did extend to ethanol. Following a series of sequential doses over 5 to 6 hr DS mice developed minimal rapid tolerance, whereas DR mice developed considerable tolerance. By the end of the day DS mice were therefore much more sensitive to ethanol than were DR mice; this difference was greater in males than in females. High dose ethanol toxicity was studied by assaying brain ethanol concentrations at the cessation of respiration; no differences were found between lines or sexes.

Animals↗
PubMed1987

Rebound hyperthermia follows ethanol-induced hypothermia in rats.

We have recently described a telemetry/microcomputer system to monitor core temperatures in rats. We implant a miniature transmitter (Mini-mitter) into the peritoneal cavity of the rat, allowing us to obtain temperatures around the clock without handling the animals or disturbing the light-dark cycle. In the present study we describe the temperature effects of ethanol doses ranging from 2 to 6 g/kg. Baseline temperatures were collected for 2 days before drug was administered. Subsequent computer analysis then allowed us to compare experimental results in each animal with its own baseline temperature to allow for individual and circadian temperature differences. In preliminary studies we observed the well-known dose-dependent hypothermic effect of ethanol. However, by observing animals continually over 4 days we also observed a period of rebound hyperthermia beginning at about the time of complete ethanol elimination and persisting for several days. During this period daytime temperatures remained at the normally high night-time level. This may be evidence of a mild abstinence syndrome, or alternatively, may be due to a disruption of the normal circadian temperature rhythm.

Alcoholic Intoxication↗
PubMed1987

Mouse lines selected for genetic differences in diazepam sensitivity.

Selective breeding techniques were used to alter allelic frequencies responsible for diazepam sensitivity and resistance. We used the rotarod test to determine the duration of diazepam-induced neurologic deficit in genetically heterogeneous mice. Males were more sensitive than females in the initial population. We then selectively bred for diazepam resistance and sensitivity. A significant difference between the lines was apparent in both sexes after two generations, and divergence has continued over seven generations. Brain benzodiazepine assays indicated that absorption and distribution of diazepam do not differ in the two lines. Differences in brain benzodiazepine concentrations at recovery from ataxia indicated that the two lines differ in central nervous system sensitivity. We found diazepam-induced rotarod impairment to be blocked in a dose-dependent manner by the specific benzodiazepine antagonist Ro 15-1788, indicating that this effect is mediated through BZ receptors. A dose-response curve obtained from generations 6 and 7 indicates a 9- to 14-fold difference in dose required to obtain similar effects in the two lines. These mice are expected to be useful experimental subjects in studies of benzodiazepine mechanisms.

Animals↗
PubMed1987

Alprazolam dependence in mice.

Mice were treated with 0.025% alprazolam incorporated into their laboratory chow for periods of one, two, and four weeks. Treated animals gained weight and appeared healthy during treatment, although an increased number of animals were lost in the treatment groups due to cannibalism. When regular food was substituted, alprazolam-treated animals experienced a withdrawal reaction qualitatively similar to that previously observed following similar lengths of treatment with 0.1% diazepam in food. The withdrawal reaction following alprazolam had a faster onset and a shorter time course, and was less intense. In a separate experiment, eight mice were treated with alprazolam for two weeks but were housed singly. This eliminated the cannibalism problem and no animals were lost during the treatment phase; the withdrawal syndrome was similar to that seen in group-housed animals. The model of benzodiazepine dependence in mice would appear to generalize to the entire class of drugs and may permit distinctions to be made between the time-course of withdrawal reactions between the various members of that class.

Alprazolam↗
PubMed1986

Benzodiazepine dependence in mice after ingestion of drug-containing food pellets.

Diazepam was administered to Swiss-Webster mice for 53 days as a mixture of drug in laboratory chow, leading to consumption as high as 1000 mg/kg/day. Low plasma concentrations of diazepam, but very high levels (generally between 5,000 and 10,000 ng/ml) of the active metabolites nordiazepam and oxazepam, were found. Animals appeared healthy throughout drug administration, but some died because of apparent drug-induced aggression. Withdrawal was precipitated by omitting drug from the food. The behavior and physiological state of each animal were observed in detail during treatment and withdrawal phases. Tests that showed stable results in control animals and changes during abstinence were used to measure the withdrawal syndrome. These changes included piloerection, tremor, pelvic elevation and tail elevation, as well as changes in body tone, abdominal tone and pupil size. A composite withdrawal score was plotted against time; this score increased significantly (P less than .01) 1 day after withdrawal and remained significantly elevated for 17 days. This technique provides a quantitative method to study the effect of withdrawal from benzodiazepines in mice.

Aggression↗
PubMed1985

Automated remote temperature measurement in small animals using a telemetry/microcomputer interface.

Temperatures can be obtained from small animals by implanting commercially available radio-telemetry probes (Mini-Mitters), thereby avoiding handling-induced artifacts. We have developed an inexpensive microcomputer interface to automatically collect data from Mini-Mitters. The interface hardware detects the signal and converts it to a TTL pulse train compatible with the Commodore PET microcomputer. The software converts the frequency to temperature, controls the sampling schedule, and can selectively measure any one of eight cages. Temperature measurements can thus be made around the clock with no technician present.

Animals↗
PubMed1984

Long-lasting single-dose tolerance to neurologic deficits induced by diazepam.

Development of single-dose tolerance to diazepam-induced neurologic deficits was assessed in mice by means of a rotarod test. Diazepam suspended in corn oil was administered orally in doses 5-20 mg/kg. Tolerance was found following a second administration of diazepam 24 h after a first dose. It decayed gradually over 4-5 weeks. Hence tolerance persists considerably longer than measurable amounts of diazepam or its metabolites are likely to be present in mice.

Administration, Oral↗
PubMed1982

The rapid onset of tolerance to ataxic effects of ethanol in mice.

We have developed a precise quantal method for assessing the sensitivity to ethanol in the mouse. Mice placed on a clamped stationary horizontal dowel are scored ataxic or not ataxic depending on whether they are able to remain on the dowel during a 30-s observation period. A threshold blood ethanol concentration is determined by assaying tail blood drawn immediately upon recovery from ethanol-induced ataxia. This threshold is quite reproducible within a population of Swiss-Webster mice (coefficient of variation 9%). The precision of this method allowed us to follow the onset of rapid tolerance during a series of sequential IP ethanol doses. Tolerance persisted overnight in the absence of ethanol, and was found not to increase further with additional ethanol exposure on 2 subsequent days. The observed tolerance was shown not to be due to circadian changes in ethanol sensitivity or repeated practice on the task, indicating a true tissue tolerance.

Animals↗