Biomedical subjects
Publications and source records attributed to L Lumeng.
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The plasma pyridoxal-5'-phosphate (PLP) level of alcoholic subjects has been compared with that of non-alcoholic individuals in order to ascertain the incidence of abnormal vitamin B(6) metabolism in chronic alcohol abuse. 66 alcoholic subjects were selected on the basis that they did not exhibit abnormal liver function tests and hematologic findings. 35 of them had plasma PLP concentrations less than 5 ng/ml, the lowest value encountered in 94 control subjects, indicating a high incidence of deranged PLP metabolism in alcoholic patients even when hepatic and hematologic abnormalities are absent. The biochemical basis for the altered PLP metabolism in chronic alcohol abuse was examined. Low plasma PLP levels in alcoholics were not accompanied by decreased pyridoxal kinase and pyridoxine phosphate oxidase activities in erythrocytes. Further studies with erythrocytes demonstrated that the cellular content of PLP is determined not only by the activities of these PLP-synthesizing enzymes but also by the activity of a phosphate-sensitive, membrane-associated, neutral phosphatase, which hydrolyzes phosphorylated B(6) compounds.Acetaldehyde, but not ethanol, impaired the net formation of PLP from pyridoxal, pyridoxine, and pyridoxine phosphate by erythrocytes. However, when the B(6)-phosphate phosphatase activity was inhibited by 80 mM phosphate, this effect of acetaldehyde was abolished. By the use of broken cell preparations, it was possible to demonstrate directly that the action of acetaldehyde is mediated by the phosphatase, resulting in an acceleration of the degradation of the phosphorylated B(6) compounds in erythrocytes.
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With the goal of obtaining a suitable animal model for voluntary oral consumption of ethanol, the investigators selectively bred lines of alcohol-preferring and alcohol-nonpreferring rats, with preference considered as a function of the concentration of ethanol ingested. Studies with these animals showed that drinking is voluntary and not contingent on caloric restriction; that they will work to obtain ethanol even when food and water are freely available, and in so doing, show psychological or behavioral tolerance; that the amount of ethanol voluntarily consumed approaches their apparent maximum capacity for ethanol elimination. This amount of ethanol was capable of altering brain neurotransmitter content, thus exerting a CNS pharmocologic effect. In addition, the rats will bar-press for intravenous administration of ethanol, and with prolonged, free-choice consumption, ethanol intake increases to as much as 12 g per kg body weight per day without producing behavioral deficits, suggesting the development of tolerance.
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The P line of alcohol-preferring rats drink pharmacologically significant amounts of ethanol when given free choice between a 10 percent ethanol solution and water. Serotonin (5-HT) uptake inhibitors and desipramine, a norepinephrine (NE) uptake inhibitor, were found to significantly reduce their ethanol consumption for up to 24 hours after intraperitoneal injection. To determine if this effect of 5-HT uptake inhibitors could be altered by receptor antagonists, some of which are short acting, P rats were trained to drink ethanol by free choice during scheduled availability, with ethanol being presented one hour every four hours during the light cycle. The majority of the ethanol was consumed during the first hour of availability, and the ethanol intake was significantly reduced by the 5-HT uptake inhibitors, fluoxetine and fluvoxamine. Pretreatment with antagonists for 5-HT1, 5-HT2 and alpha- and beta-NE receptor systems failed to alter the fluvoxamine attenuation of ethanol intake. The mechanism by which 5-HT uptake inhibitors alter ethanol preference remains unclear.
Recent reports have described increased levels of a fast-moving hemoglobin (Hb) fraction in alcoholic patients and formation in vitro of stable adducts between acetaldehyde and Hb as well as between acetaldehyde and albumin. In the present study, we have found that factors other than acetaldehyde concentration can influence the rate of stable adduct formation. HbAo was purified and its 2,3-diPglycerate removed by dialysis. Under anaerobic condition and at 37 degrees, acetaldehyde (5 microM) reacted with deoxyHbAo to form 0.26 +/- 0.02 (+/- SEM) nmol of stable adduct/149 nmol Hb in 2 hr. By comparison, acetaldehyde reacted more slowly with oxyHbAo and carbonylHbAo; the rates were 0.21 +/- 0.01 (p less than 0.001) and 0.18 +/- nmol/149 nmol Hb/2 hr (p less than 0.001), respectively. Pyridoxal 5'-phosphate (50-500 microM), under anaerobic condition, inhibited by 36-56 percent the irreversible binding of acetaldehyde to deoxyHbAo. Ascorbic acid (2.5-10 mM) increased by 31-46 percent (p less than 0.001) the irreversible binding of acetaldehyde to human serum albumin and by 8-10 percent (p less than 0.05) the irreversible reaction of acetaldehyde with serum proteins. We conclude that the nonenzymatic binding of acetaldehyde to Hb, human serum albumin and serum proteins is influenced by factors other than acetaldehyde concentration. These factors include oxygen tension, pyridoxal 5'-phosphate and ascorbic acid. Among these factors, oxygen tension may be the most important in vivo.
The effects of scheduling the availability of ethanol on its voluntary consumption by the selectively bred alcohol-preferring P rats were examined under three conditions: unrestricted 24 hr/day access (Condition A), access limited to a continuous 4 hr/day (Condition B), and access limited to 1 hr every 3 hr, 4 times/day (Condition C). Food and water were always available. Daily alcohol intakes (mean +/- SEM) with Conditions A, B and C were 6.9 +/- 0.2, 2.1 +/- 0.2 and 4.4 +/- 0.2 g/kg, respectively, while the intake per hour of availability increased from 0.3 +/- 0.03 under Condition A to 1.1 +/- 0.4 g/kg under condition C. The amount of ethanol consumed per drinking episode under Conditions A, B and C were 1.1 +/- 0.1, 2.1 +/- 0.2 and 1.1 +/- 0.03 g/kg, respectively. Mean blood alcohol concentrations (BACs), determined periodically during the dark cycle of Condition A and five minutes after drinking episodes under Conditions B and C, were 59 +/- 10, 61 +/- 7 and 62 +/- 7 mg%, respectively. When unlimited access was reinstated after Condition C, daily alcohol consumption returned to a level similar to that under the initial Condition A (7.2 +/- 0.5 g/kg). When the ethanol concentration was increased from 5 to 20% (v/v) under Condition C, the amount of ethanol consumed per episode at 5% was significantly less than at the 10, 15 and 20% concentrations, and the volume consumed was significantly lower at the 20% concentration than at the 5, 10 and 15% concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Rats of the alcohol-preferring P line (n = 7) were trained to self-administer ethanol (20% v/v) and water via an intragastric IG catheter. Food was available ad lib. Ethanol intakes averaged approximately 5-6 g/kg body wt./day. Treatment with the serotonin (5-HT) uptake inhibitor fluoxetine (10 mg/kg/day; IG) for seven consecutive days produced a marked decrease in ethanol self-administration on the first day, which was sustained throughout the seven days of treatment to values as low as 1 g/kg/day. Concomitant with the decrease in ethanol intake, the self-infusion of water gradually increased during the period of fluoxetine treatment. Total caloric intake (ethanol plus food) was moderately reduced during fluoxetine treatment; the decrease in food consumption was consistent but not statistically significant. When fluoxetine treatment was terminated, ethanol self-administration quickly returned to the prefluoxetine levels, while water intake began to decrease. Since no ethanol was consumed orally, the IG ethanol was not self-administered for its taste or smell, but apparently for its postingestive pharmacological effects. The robust reduction of ethanol self-infusion that occurred with fluoxetine treatment suggests that the 5-HT systems are involved in the reinforcing effects of ethanol in the P line of rats.
Rats of the P (n = 4) and NP (n = 5) lines were housed in operant chambers with food available ad lib, but all liquid was obtained by responding on either of two levers according to a FR5 schedule. Presses on one lever produced water from an automated dipper, while the other lever gave access to a dipper containing ethanol in concentrations ranging from 2 to 30% (v/v). P rats worked to obtain the ethanol at all concentrations offered and preferred the ethanol over water. The highest ethanol intake averaged 7.7 +/- 0.5 g/kg body weight/day at the 15% concentration and at least 5.8 +/- 0.9 g/kg/day for the 20-30% range. The NP rats responded more for the 2 and 5% concentrations of ethanol than for water, but responded predominantly for water when the ethanol concentrations were 10% and higher. In a second experiment, NP rats drank water rather than 10% ethanol by free-choice, even though the ethanol was mixed with a preferred flavor and the water with a nonpreferred flavor. The findings indicate that ethanol is rewarding to P rats in concentrations up to 30% (v/v) but is not rewarding to NP rats when the concentration is 10% and above.
The contents of dopamine (DA), serotonin (5-HT) and their primary acid metabolites were assayed in ten brain regions of the selectively bred high-alcohol drinking (HAD) and low-alcohol drinking (LAD) lines of rats. Compared with the LAD line, the contents of 5-HT and/or 5-hydroxyindoleacetic acid were approximately 10-20% (p less than 0.05) lower in several brain regions of the HAD line (cerebral cortex, striatum, nucleus accumbens, septal nuclei, hippocampus and hypothalamus). The levels of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid were also 10-20% lower in the nucleus accumbens and anterior striatum (p less than 0.05) of the HAD animals. These data are in agreement with previous findings that comparatively lower levels in 5-HT and DA systems are associated with high-alcohol drinking in rodents and support the involvement of certain 5-HT and DA pathways in the mediation of alcohol drinking behavior.
Neurochemical and neuropharmacological studies were undertaken to assess the involvement of CNS serotonin (5-HT), dopamine (DA) and GABA systems in regulating the alcohol-drinking behavior of two lines of rats selectively bred for their high alcohol-seeking behavior, namely the alcohol-preferring P line and the high alcohol-drinking HAD line of rats. Neurochemical data indicate that high alcohol-seeking behavior (when compared with data from rats with low alcohol-seeking characteristics) is associated with: a) lower (10-20%; p less than 0.05) contents of 5-HT in certain limbic regions (e.g., nucleus accumbens, frontal cortex, hypothalamus and hippocampus); b) a lower (10-15%; p less than 0.05) content of DA in the nucleus accumbens; c) higher (20-35%; p less than 0.05) densities of 5-HT1A binding sites in some limbic regions (e.g., medial nucleus accumbens, medial prefrontal cortex and ventral hippocampus); and d) a greater (20-50%) density of GABA axon terminals in the nucleus accumbens. Furthermore, the acute administration of high doses of ethanol appears to increase the activity of the 5-HT and DA projections to the nucleus accumbens of the P line of rats (as indicated by the 20-30% elevated tissue levels of 5-HT and DA metabolites following IP ethanol administration); neuronal tolerance to alcohol appears to develop in both these monoamine pathways, as suggested by an attenuated effect on metabolite levels by a challenge dose of ethanol given to P rats that had been chronically drinking alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)