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Biomedical subjects

L Lumeng

Publications and source records attributed to L Lumeng.

At least 73 records · Page 4Linked to original sources
PubMed1997

Alcohol intake of P rats is regulated by muscarinic receptors in the pedunculopontine nucleus and VTA.

Experiments were conducted to determine whether muscarinic receptors within the pedunculopontine nucleus (PPN) and ventral tegmental area (VTA) are involved in regulating ethanol drinking behavior in the alcohol-preferring P line of rats. Female P rats were given limited access (2 h/day) to 10% (v/v) ethanol and 0.0125% (g/100 ml) saccharin solutions. Food was available ad libitum. Cholinergic agents were microinjected unilaterally into the PPN or VTA immediately prior to ethanol access. Intra-PPN carbachol (1-4 microg/0.5 microl), which can inhibit cholinergic neuronal activity within the PPN, decreased ethanol (70% decrease at the highest dose; p < 0.05) and saccharin (90% decrease at the highest dose; p < 0.05) intake in a dose-dependent manner within the first 30 min. Intra-PPN scopolamine (5-15 microg/0.5 microl), which can stimulate cholinergic neuronal activity within the PPN, decreased ethanol intake in a dose-dependent manner within the first 30 min (65% decrease at the highest dose; p < 0.05) without reducing saccharin intake. Intra-VTA methylscopolamine (1-10 microg/0.5 microl), a muscarinic antagonist, significantly (p < 0.05) reduced ethanol (60% decrease at the highest dose) and saccharin (50% decrease at the highest dose) intakes during the 2-h access period. Intra-VTA carbachol, a cholinergic agonist (1 and 2 microg/0.5 microl) decreased ethanol consumption in a dose-dependent manner within the first 60 min (50% decrease at the highest dose) without reducing saccharin intake. Overall, these results support an involvement of the cholinergic PPN-VTA system in regulating alcohol drinking and general consummatory behaviors of the P line of rats.

Alcohol Drinking↗
PubMed1997

6-OHDA-lesions of the nucleus accumbens disrupt the acquisition but not the maintenance of ethanol consumption in the alcohol-preferring P line of rats.

The aim of the present study was to determine whether reduction of dopamine (DA) innervation to the nucleus accumbens (ACB) alters the maintenance and/or acquisition of ethanol drinking in female alcohol-preferring P rats. Compared with sham-lesioned animals, bilateral microinjections of 6-OHDA (12 micrograms/2.4 microliters/site) into the ACB did not alter the consumption of 10% ethanol in rats that had prior experience of ethanol drinking, with both sham- and 6-OHDA-lesioned groups recovering to presurgical consumption levels at similar rates. On the other hand, the identical lesion procedure disrupted the acquisition of ethanol intake in rats with no ethanol-drinking experience prior to the lesions. A sham-lesioned group attained an ethanol intake of approximately 7 g/kg/day in 1 week, which was maintained over the following 2-week period, while the ethanol intake of the 6-OHDA-lesioned group was approximately 60% lower after 1 week and 30% lower at the end of 3 weeks. DA content of the ACB was 60% lower in both groups of the 6-OHDA-treated rats compared with the controls. The results suggest that different neural mechanisms may underlie the acquisition and maintenance of ethanol drinking behavior; the ACB DA system appears to play an important role in the acquisition of ethanol drinking.

Adrenergic Agents↗
PubMed1996

Effects of the benzodiazepine inverse agonist RO19-4603 alone and in combination with the benzodiazepine receptor antagonists flumazenil, ZK 93426 and CGS 8216, on ethanol intake in alcohol-preferring (P) rats.

The present study investigated dose dependence and time course effects of the benzodiazepine (BDZ) partial inverse agonist, RO19-4603 (0.005-0.30 mg/kg) alone, and in combination with the BDZ receptor antagonists flumazenil, ZK 93426, and CGS 8216 (20 mg/kg) in selectively bred alcohol-preferring (P) rats provided a two-bottle choice test between ethanol (EtOH) (10% v/v), and a palatable saccharin (0.0125% g/v) solution. A single dose of RO19-4603 as low as 0.009 mg/kg selectively reduced EtOH drinking during the initial 15 min of a 4 h access to 19-0% of control levels on day 1. The 0.08, 0.15 and 0.30 mg/kg doses of RO19-4603 significantly reduced total EtOH intake in the 4 h access period to 57-45% of controls on day 1. On day 2, no RO19-4603 injections were given; however, six of the seven doses of RO19-4603 (0.009, 0.02, 0.04, 0.08, 0.15, and 0.30 mg/kg) continued to reduce EtOH intake to 42-3% of control levels at the initial 15 min interval, while the 0.005, 0.009, 0.08, and 0.30 mg/kg doses reduced total 4 h EtOH intake to 60-42% of controls. Saccharin intake was either not altered by RO19-4603 or showed increases during the initial 15 min intervals and the total 4 h sessions on days 1 and 2. Food intake was also unaffected by RO19-4603. The CGS 8216, but neither flumazenil nor ZK 93426, reliably reversed the RO19-4603-induced suppression of EtOH intake on days 1 and 2. That certain BDZ inverse agonists can attenuate motivated behavior for EtOH reinforcement over a prolonged time course may provide a possible therapeutic approach to reducing EtOH consumption associated with alcoholism.

Alcohol Drinking↗
PubMed1996

Identification of the 37-kd rat liver protein that forms an acetaldehyde adduct in vivo as delta 4-3-ketosteroid 5 beta-reductase.

Acetaldehyde, the first product of alcohol metabolism, is highly reactive. Several proteins have been shown to be covalently modified by acetaldehyde in vivo. We have previously reported the detection of a cytosolic 37-kd protein-acetaldehyde adduct (-AA) in the liver of alcohol-fed rats. The liver extract from an alcohol-fed rat was subjected to 2-dimensional (2D) sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis (PAGE), transferred to polyvinylidene difluoride (PVDF) membrane, and the 37-kd protein-AA spot was digested with trypsin and sequenced for amino acids. Degenerate oligonucleotides corresponding to a peptide sequence of the protein-AA were used as the probe to screen a lambda gt11 rat liver complementary DNA (cDNA) library. A clone that extended to a potential ATG start codon was identified. The open reading frame was 978 nucleotides long, encoding 326 amino acid residues. The sequence matched that of rat liver delta 4-3-ketosteroid 5 beta-reductase. The cloned cDNA was expressed in Escherichia coli using pGEX-KG as the vector. The expressed protein was found to be of correct molecular weight. It reacted with an antibody that recognized the unmodified liver 37-kd protein by Western blotting. Peptide profiles of tryptic-digested recombinant protein and the purified rat liver 37-kd protein were similar and yielded the same peptide sequence. delta 4-3-ketosteroid 5 beta-reductase catalyzes the reduction of key intermediates during bile acid biosynthesis. Whether modification of the 5 beta-reductase by acetaldehyde affects the enzyme activity and bile acid synthesis remains to be studied.

Acetaldehyde↗
PubMed1996

Place conditioning with alcohol in alcohol-preferring and -nonpreferring rats.

A place-conditioning procedure was used to examine the effect of selective breeding for ethanol preference on sensitivity to the rewarding and/or aversive effects of ethanol. On 4 alternate days, groups of seven to eight alcohol-preferring (P) and alcohol-nonpreferring (NP) rats received IP injections of 0.0 (saline controls), 0.5, 1.0, or 1.5 g ethanol/kg body wt. immediately before 15-min confinement in a novel environment. On the 4 intervening days the same rats received saline injections before 15 min confinement in a different environment. On day 9, a 15-min choice test was given with no injections, in which the rats could move freely between the ethanol and the saline-paired environments. Dose-dependent avoidance of the ethanol-paired environment was observed in both lines of rats (1.0 and 1.5 g/kg), but the magnitude of the avoidance was less in the P relative to the NP rats, indicating that ethanol was less aversive for the P rats. No evidence for a place preference was observed in either line with any of the ethanol doses. An innate reduced sensitivity to the aversive effects of ethanol in rats of the P line and/or an enhanced sensitivity to the aversive effects of ethanol in rats of the NP line may contribute to the different levels of oral ethanol self-administration observed in these selectively bred rat lines.

Animals↗
PubMed1996

Characterization of a new hereditary thrombopathy in a closed colony of Wistar rats.

A new hereditary thrombopathy has been identified in a closed colony of Wistar rats. A simple and reproducible cuticle bleeding time test was developed as a rapid screening procedure for the bleeding diathesis. Affected animals exhibit markedly prolonged bleeding times and complete absence of platelet aggregation either with adenosine diphosphate (ADP) or with thrombin. Inheritance data suggest an autosomal dominant inheritance pattern with variable penetrance. Coagulation tests, platelet counts, plasma von Willebrand factor (vWF) activity, and clot retraction are within normal limits in thrombopathic animals. GPIb-dependent botrocetin-induced platelet agglutination was present in washed thrombopathic rat platelets. No discernible abnormality of intraplatelet organelles or granules was seen by transmission electron microscopy of thrombopathic platelets. A qualitative morphologic assessment of intraplatelet fibrinogen in thrombopathic rat platelets showed no discernible difference as compared with control rat platelets. Thrombopathic rat platelets exhibit decreased glycoprotein IIb/IIIa (GPIIb/IIIa) antigen by flow cytometric analysis and markedly decreased iodine 125-labeled fibrinogen binding to platelet GPIIb/IIIa after ADP activation. This rat colony demonstrates a unique thrombopathy, distinct from previously described animal thrombopathies, with some characteristics of variant Glanzmann's thrombasthenia. This animal model may provide further insight into the regulatory mechanisms and pathophysiology of platelet GPIIb/IIIa.

Animals↗
PubMed1996

Benzodiazepine receptor ligands with different intrinsic efficacies alter ethanol intake in alcohol-nonpreferring (NP) rats.

Benzodiazepine (BDZ) receptor ligands with varying intrinsic efficacies [RO19-4603, 0.02-0.15 mg/kg; FG 7142 1-16 mg/kg; DMCM, 1-8 mg/kg; RO16-6028 (bretazenil), 8-32 mg/kg] in modulating GABAergic activity were examined for the ability to alter palatability-induced ethanol (EtOH) intake in the alcohol-nonpreferring (NP) line of rats. NP rats on a 22-hour fluid-deprivation schedule were given 2-hour daily access to a 10% (v/v) EtOH/3% (g/v) polycose solution and water. Average EtOH intake was 2.1 +/- 0.2 g/kg/2 hours, and water intake was 17.1 +/- 0.9 ml/2 hours. During the initial 15 minutes of the 2-hour session, RO19-4603, the imidazothienodiazepine partial inverse agonist reduced EtOH intake to 19% of control values at 0.04 mg/kg and completely suppressed drinking of the EtOH solution at 0.15 mg/kg. Twenty-four-hour postdrug administration, the 0.08-mg/kg dose of RO19-4603 completely suppressed drinking of the EtOH solution at the 60-minute interval, and the 0.15-mg/kg dose reduced intake to 20% of control levels at the 15-minute interval. FG 7142, the partial beta-carboline inverse agonist reduced EtOH drinking at the 60-minute interval with the 1-mg/kg dose, and the 16-mg/kg dose reduced water intake at the 15-minute interval. DMCM, the full beta-carboline inverse agonist, significantly reduced water intake at 15 minutes (4 and 8 mg/kg), and the same doses caused a substantial increase in EtOH drinking at the 120-minute interval. The anxiolytic agent bretazenil (16 and 32 mg/kg) increased EtOH consumption during the initial 15 minutes to 270% to 425% of control levels, and water intake increased by the end of the 2-hour session to as much as 210% of control following administration of the 32-mg/kg dose. These findings support existing evidence suggesting that BDZ receptor ligands may modify neuronal processes that mediate some reinforcing and/or aversive properties of alcohol. They further demonstrate a potential importance of the GABAA-BDZ receptor complex in mediating palatability- (environmentally) induced EtOH drinking even in rats selectively bred for low alcohol preference.

Analysis of Variance↗
PubMed1996

Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior.

Alcohol naive rats from lines genetically selected for high and low alcohol drinking and founded on either Wistar (P/NP lines) and distinct heterogeneous stocks (AA/ANA and replicate HAD/LAD lines) were tested in the explorative cross-maze and the inescapable slip funnel. Rats of the low alcohol-consuming ANA, NP, LAD1 and LAD2 lines all exhibited a shorter latency before initiating exploration of the maze than did their high alcohol-consuming counterparts (66, 51, 33 and 51% of the values for AA, P, HAD1 and HAD2 lines, respectively). Significant line differences were also found with the slip funnel test (AA > ANA for time in a sprawling posture; P > NP but HAD1 < LAD1 and HAD2 < LAD2 for time escaping), but the directions of line differences were not consistently related to those in alcohol drinking.

Journal Article↗
PubMed1996

Isoflavonoid compounds extracted from Pueraria lobata suppress alcohol preference in a pharmacogenetic rat model of alcoholism.

The extract from an edible vine, Pueraria lobata, has long been used in China to lessen alcohol intoxication. We have previously shown that daidzin, one of the major components from this plant extract, is efficacious in lowering blood alcohol levels and shortens sleep time induced by alcohol ingestion. This study was conducted to test the antidipsotropic effect of daidzin and two other major isoflavonoids, daidzein and puerarin, from Pueraria lobata administered by the oral route. An alcohol-preferring rat model, the selectively-bred P line of rats, was used for the study. All three isoflavonoid compounds were effective in suppressing voluntary alcohol consumption by the P rats. When given orally to P rats at a dose of 100 mg/kg/day, daidzein, daidzin, and puerarin decreased ethanol intake by 75%, 50%, and 40%, respectively. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total fluid volume consumed daily remained unchanged. The effects of these isoflavonoid compounds on alcohol and water intake were reversible. Suppression of alcohol consumption was evident after 1 day of administration and became maximal after 2 days. Similarly, alcohol preference returned to baseline levels 2 days after discontinuation of the isoflavonoids. Rats receiving the herbal extracts ate the same amounts of food as control animals, and they gained weight normally during the experiments. When administered orally, none of these compounds affected the activities of liver alcohol dehydrogenase and aldehyde dehydrogenase. Therefore, the reversal of alcohol preference produced by these compounds may be mediated via the CNS. Data demonstrate that isoflavonoid compounds extracted from Pueraria lobata is effective in suppressing the appetite for alcohol when taken orally, raising the possibility that other constituents of edible plants may exert similar and more potent actions.

Alcohol Dehydrogenase↗
PubMed1996

Effects of taste aversion training on the acquisition of alcohol drinking in adolescent P and HAD rat lines.

Early alcohol drinking has been hypothesized to cause alcohol-related problems in adulthood. In addition, a potential role for genetic factors exist in the etiology of some types of alcoholism. The objective of the present study was to determine if taste aversion training to ethanol during adolescence in previously ethanol-naive, alcohol-preferring P and high-alcohol drinking HAD-1 lines of rats would retard or prevent the onset of high alcohol drinking. Taste aversion training began at 30 days of age. Male and female rat pups were fluid deprived for 24 hr before 30 min access to a 10% [v/v] ethanol solution, followed by an intraperitoneal injection of either saline or 0.15 M LiCl (10 ml/kg). A total of five training sessions were administered every other day with unrestricted access to water on intervening training days. Twenty-four hours after the last training trial, rats were given continuous free-choice between water and 10% ethanol for 4 weeks with food available and libitum. There were no obvious gender or line differences to the effects of taste aversion training. All LiCl-treated subjects avoided the usually preferred ethanol solution for the entire 4-week test period, whereas saline-treated rats steadily increased their alcohol intake to over 6.0 g/kg/day by week 4. Rats in the saline and LiCl-treated groups gained weight at comparable rates, and the groups did not differ in total fluid intake. The findings demonstrate that early environmental intervention can prevent the onset of high alcohol drinking in the selectively bred alcohol-preferring P and high-alcohol drinking HAD-1 lines of rats.

Age Factors↗
PubMed1996

Effects of cholinergic agents on locomotor activity of P and NP rats.

Experiments were undertaken to compare the selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines for differences in the locomotor activity (LMA) response to intracerebroventricular infusions of muscarinic- and nicotinic-cholinergic agents. Scopolamine, a nonselective muscarinic antagonist (40 to 120 micrograms/0.5 microliters), dose-dependently increased LMA in both P and NP rats (up to 90 to 100% above baseline; p < 0.05). On the other hand, pirenzepine, a selective M1 muscarinic antagonist (10 to 80 micrograms/0.5 microliters), decreased LMA in P and NP rats (as much as 35 to 40% below control values; p < 0.05). Mecamylamine, a nicotinic antagonist (20 to 80 micrograms/0.5 microliters), also decreased LMA in P and NP rats (as much as 30 to 40% below baseline; p < 0.05). The agonist nicotine (20 to 80 micrograms/0.5 microliters) dose-dependently decreased LMA in both P and NP rats (to a maximum of approximately 60 to 65% below control values; p < 0.05). Based on standardized z-scores, NP rats were more sensitive (p < 0.05) to the locomotor depressant effects of nicotine than P rats, whereas no differences were observed for standardized z-scores between the P and NP lines on the effects of scopolamine, pirenzepine, or mecamylamine on LMA. The results suggest that subtypes of muscarinic and nicotinic receptors are involved in regulating LMA in a complex manner, with the M1 subtype possibly mediating behavioral activation, and that P and NP rats may possess innate differences in CNS nicotinic receptors regulating LMA.

Alcohol Drinking↗
PubMed1996

Serotonin2C receptors and serotonin2C receptor-mediated phosphoinositide hydrolysis in the brain of alcohol-preferring and alcohol-nonpreferring rats.

To examine the role of serotonin2C (5HT2C) receptors in alcohol drinking behavior, the binding indices of 5HT2C receptors were determined in various brain regions of alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. 5HT2C receptor-mediated phosphoinositide hydrolysis in the choroid plexus of P and NP rats was also determined. It was observed that the densities of 5HT2C receptors are significantly higher in the hippocampus, the amygdala, and the choroid plexus, but not in the cortex of P rats compared with NP rats. The Kd values of [3H]mesulergine binding to 5HT2C receptors were not different in these brain regions of P rats compared with NP rats. It was also observed that 5HT-stimulated [3H]inositol 1-phosphate formation was significantly higher in the choroid plexus of P rats compared with NP rats. The results of this study indicate that the numbers of 5HT2C receptors are higher in the hippocampus, the amygdala, and the choroid plexus, and that 5HT2C receptor-mediated phosphoinositide hydrolysis is more elevated in the choroid plexus of P rats compared with NP rats. Thus, it seems from these results that increased 5HT2C receptors may be involved in the genetic vulnerability to alcohol drinking behavior.

Alcohol Drinking↗
PubMed1996

Transjugular intrahepatic portosystemic shunt procedure: efficacy of 10-mm versus 12-mm Wallstents.

PURPOSE: To compare results of transjugular intrahepatic portosystemic shunt (TIPS) placement with 10- and 12-mm Wallstents. MATERIALS AND METHODS: Forty-six TIPS procedures in 47 patients were retrospectively reviewed. Wallstents that were 10 mm in diameter were used in 23 patients, and those that were 12 mm in diameter were used in 23 patients. Immediate results were compared, which included initial portosystemic gradient and Doppler measurements of blood flow velocity through the shunt at 1 day. Long-term patency and velocities were also assessed. RESULTS: TIPS were successfully created in 46 of 47 patients (98%). In one patient in the 10-mm group, the portal vein could not be accessed. When compared with TIPS in the 10-mm group, TIPS placed in the 12-mm group required dilation to larger diameters (mean, 11.1 vs 9.2 mm; P < .0001) to achieve an identical target gradient of 10 mm Hg and exhibited lower 1-day velocities (mean, 1.3 m/sec vs 1.7 m/sec; P < .03). The 1-day occlusion rate was 17% (four of 23 patients) in the 12-mm group versus 0% in the 10-mm group (P < .02). Patient survival was statistically significantly less in the 12-mm group (P < .03). CONCLUSION: Twelve-millimeter Wallstents yield statistically significantly poorer short- and long-term results in TIPS procedures. This is most likely due to the decreased radial strength of the larger stent, which is 50% less than that of the 10-mm stent.

Adolescent↗
PubMed1996

Metabolic problems in recipients of liver transplants.

We analyzed the metabolic problems in recipients of liver transplants. Immunosuppression consisted of cyclosporine, steroids and azathioprine. With a mean follow up of 3.5 yr, 37% of 71 recipients were rendered permanently diabetic and hyperlipidemic. Recipients who developed posttransplant diabetes had higher cholesterol levels and proteinuria, but decreased creatinine clearance. Transplant recipients who developed posttransplant hyperlipidemia had greater proteinuria, but their sugars and creatinine clearance were comparable to those who did not have hyperlipidemia. The most significant factor responsible for these metabolic complications was the total dosage of prednisone and cyclosporine. There was no effect of risk antigens on the development of diabetes.

Adult↗
PubMed1995

Calcitonin gene-related peptide (CGRP) content and CGRP receptor binding sites in discrete forebrain regions of alcohol-preferring vs. -nonpreferring rats, and high alcohol-drinking vs. low alcohol-drinking rats.

This study showed that alcohol-preferring (P) rats and high alcohol-drinking (HAD) rats possess fewer calcitonin gene-related peptide (CGRP) receptor binding sites than their respective controls in the central amygdaloid nucleus (CeA) which is known to be related to anxiety. Since P and HAD rats are selectively bred for high alcohol preference, and alcohol can produce anxiolytic effect, one can postulate that P and HAD rats preferentially drink alcohol in order to obtain its anxiolytic effect. This study supports a hypothesis that deficit of CGRP receptors in the CeA of P and HAD rats may contribute to alcohol preference.

Amygdala↗
PubMed1995

Insulin autoimmune syndrome as a cause of spontaneous hypoglycemia in alcoholic cirrhosis.

Hypoglycemia in fulminant hepatic failure and hyperinsulinemia in cirrhosis are well-described phenomena. A patient with alcoholic cirrhosis who developed fasting hypoglycemia with an extremely high immunoreactive insulin level and a mildly elevated C-peptide level is reported. An insulinoma was excluded by detailed radiological imaging of the pancreas and by endoscopic ultrasonography. Detection of very high levels of insulin autoantibodies with no prior exposure to exogenous insulin confirmed the diagnosis of insulin autoimmune syndrome. During his hospital course, the patient developed another rare syndrome, acquired inhibitors to factor V, which led to the fatal coagulopathy that resulted in his death. Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemia in Japan, where it has been associated with a variety of diseases and drugs. Outside of Japan, only approximately 20 cases have been reported and usually have been found in the context of an underlying autoimmune disorder or prior exposure to sulfhydryl drugs. It is believed that this is the first case reported outside Japan occurring in association with alcoholic liver disease, and the first in the world with coexisting acquired inhibitors to factor V.

Autoimmune Diseases↗