A polymorphism in the rat liver mitochondrial ALDH2 gene is associated with alcohol drinking behavior.
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Alcohol Drinking↗
Biomedical subjects
T K Li
Publications and source records attributed to T K Li.
Importance of delta opioid receptors in maintaining high alcohol drinking.
We have previously reported that naloxone, a nonspecific opioid receptor antagonist, suppresses alcohol but not water consumption by male rats that have been genetically selected for high voluntary alcohol drinking. However, the identity of the specific opioid receptor subtype that may mediate alcohol drinking is not known. This paper reports that a selective delta opioid receptor antagonist is as effective as naloxone in suppressing alcohol consumption and that an enkephalinase inhibitor, which potentiates the action of endogenous enkephalins, increases alcohol intake. These results suggest that alcohol-induced activation of the endogenous enkephalinergic system, and occupation of delta opioid receptors, are involved in the maintenance of continued alcohol drinking.
Alcohol Drinking↗
Chronic alcohol consumption in alcohol-preferring P rats attenuates subsequent conditioned taste aversion produced by ethanol injections.
Rats of the P line were tested for the development of tolerance to the aversive effects of ethanol during 33 days of continuous availability of food, water and a 10% (v/v) ethanol solution. Beginning on the day following the removal of ethanol, five daily conditioned taste aversion (CTA) trials were administered to the ethanol-drinking P rats and an ethanol-naive control group. The CTA trials consisted of a 20-min access to a Polycose solution, followed by IP injection of saline, 0.5, 1.0, or 1.5 g ethanol/kg. The ethanol-drinking rats developed a preference for the Polycose solution when it was paired with 0.5 g ethanol injections, but the control rats did not. Both control and ethanol groups had similar CTAs at the 1.5 g dose. However, at the 1.0 g dose, the ethanol group had an attenuated CTA compared with the water control group. The results suggest that P rats develop tolerance to aversive effects of ethanol during chronic drinking. This tolerance could contribute to the high ethanol intake in these selectively-bred rats.
Alcohol Drinking↗
Electrophysiological response to ethanol in P and NP rats.
Event-related potentials (ERPs) have been successfully used in human subjects to evaluate alcoholics as well as those at risk for the future development of alcoholism. In the present study, two lines of rats, those with a preference for ethanol consumption (P) and those not preferring (NP) to drink ethanol were studied using ERP-producing stimuli. Rats were implanted with electrodes in the frontal cortex and dorsal hippocampus (DHPC). A passive auditory "oddball" paradigm was used to record ERP responses following saline and two doses (0.5, 1.0 g/kg) of ethanol. P and NP rats differed under the saline condition in that P rats had smaller N1-like ERP components and larger P2 waves in both cortex and hippocampus. P and NP rats were also found to differ in response to ethanol administration. NP rats evidenced dose-dependent reductions in ERP component amplitudes such as the N1 recorded from cortical sites. P rats did not have such reductions in N1 amplitudes and in fact, displayed increased N1 amplitudes in hippocampal sites. These studies provide further electrophysiological evidence that rats with a genetically influenced preference for ethanol consumption differ from nonpreferring rats at baseline and have a less intense depressant or more stimulating response to ethanol challenge.
Alcohol Drinking↗
Polymorphism of the rat liver mitochondrial aldehyde dehydrogenase cDNA.
In humans, a deficiency in mitochondrial aldehyde dehydrogenase (Class 2 ALDH) activity due to a single base-pair exchange in its structural gene serves as a deterrent to excessive alcohol consumption. Differences in Class 2 ALDH isozyme patterns on isoelectric focusing gels have been observed in the selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) lines of rats. To determine whether the differences are the result of sequence variation in the structural gene, we sequenced the cDNAs for Class 2 ALDH from P and NP rats. A synonymous exchange was seen in the codon for amino acid 473 in both lines, when compared with published sequences. Additionally, when the cDNA from P rats was used as reference, a substitution (G for A) was identified in the cDNA of NP rats which changes amino acid 67 from Gln (CAG codon; ALDH2Q allele) to Arg (CGG codon; ALDH2R allele). The Arg for Gln substitution makes the enzyme more basic and could account for the different electrophoretic mobilities. To determine whether the polymorphism was associated with drinking behavior, we genotyped the ALDH2 locus by amplifying rat genomic DNA encompassing the nucleotide exchange followed by probing with allele-specific oligonucleotides. There are highly significant differences in the frequencies of the two alleles in the P and NP rat lines. The frequency of the ALDH2R allele is 63% in the NP line and only 18% in the P line, whereas the frequency of the ALDH2Q allele is 82% in the P line and 37% in the NP line.
Alcoholism↗
The effects of ethanol initiation procedures on ethanol reinforced behavior in the alcohol-preferring rat.
Rats from the alcohol preferring (P) line developed at Indiana University were initiated to self-administer ethanol orally without food or water restriction using either a sucrose-fading or a secondary-conditioning procedure. Following initiation, they were tested under a variety of operant conditions to examine the ability of ethanol to reinforce lever pressing behavior. Regardless of initiation procedure, the animals maintained lever pressing behavior with ethanol reinforcement, even at ethanol concentrations as high as 40% (v/v). Slightly higher daily session intakes (g/kg) were found at the higher ethanol concentrations following the secondary-conditioning initiation procedure compared with the sucrose-fading technique. When both ethanol and water were concurrently available, the rats showed a high preference for ethanol reinforcement. When varying concentrations of sucrose were substituted for water, the amount of ethanol ingested decreased as the concentration of the alternative sucrose increased. However, if the response requirement for the sucrose was substantially greater than that for ethanol, the rats shifted their responding to the lever associated with ethanol presentation. The results are discussed in relation to prior work using similar procedures with Long-Evans non-selected rats and with the alcohol non-preferring (NP) rat line.
Alcohol Drinking↗
An unusual presentation of a high-grade, non-Hodgkin's lymphoma in the maxilla.
A case of a high-grade, non-Hodgkin's lymphoma affecting the maxillary alveolus which exhibited the classical radiological features of a malignant lesion occurring in the jaws is presented. CT demonstrated considerable upward displacement of an expanded but intact antral floor. Such a feature is more usually suggestive of involvement of the antrum by a benign lesion arising within the alveolar bone.
Adult↗
Animal models for the study of alcoholism: utility of selected lines.
One recent advance in the field of alcohol research has been the recognition that a predisposition to develop alcoholism is, in part, genetically determined. It now remains to identify the factors, which, when inherited, increase risk for alcoholism. One approach to this problem is to analyze how organisms with identifiable genetic predisposition towards ethanol drinking differ from organisms without genetic risk. Such an approach may lead to the identification of neurochemical, neurophysiological or neuroanatomical factors which, when inherited alone, or in combination, serve to predispose an organism towards ethanol drinking.
Alcohol Drinking↗
Serotonin and dopamine systems regulating alcohol intake.
Neurochemical and neuropharmacological studies were undertaken to assess the involvement of CNS serotonin (5-HT) and dopamine (DA) pathways in regulating the alcohol intake of rats selectively bred for their high alcohol seeking behavior (P and HAD lines). Neurochemical data indicate that high alcohol seeking behavior (when compared with data from rats with low alcohol seeking characteristics) is associated with (a) lower contents of 5-HT in certain limbic regions, e.g., n. accumbens (Acb), frontal cortex, (b) a lower content of DA in the Acb, and (c) higher densities of 5-HT1A receptors in certain limbic regions, e.g., cerebral cortex. Neurochemical data also suggest that ethanol can activate the DA and 5-HT systems projecting to the Acb. Neuropharmacological studies demonstrated that local microinfusion of a 5-HT agonist into the Acb of the P line of rats enhanced ethanol drinking. Intracranial self-administration studies established that P rats will self-administer ethanol directly into the ventral tegmental area (VTA). Overall the data suggest the involvement of certain VTA DA and dorsal raphe nucleus 5-HT pathways in regulating high alcohol drinking behavior.
Alcohol Drinking↗
Molecular associations of alcohol-seeking behavior in rat lines selectively bred for high and low voluntary ethanol drinking.
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Alcohol Drinking↗
Microinjection of sulpiride into the nucleus accumbens increases ethanol drinking in alcohol-preferring (P) rats.
The effects of dopamine antagonists microinjected into the nucleus accumbens (Acb) on alcohol-drinking behavior were studied in the selectively bred alcohol-preferring (P) line of rats. P female rats (N = 8) were given access to food and water ad lib, while availability of a 10% (v/v) ethanol solution was limited to 1 hr/day. After implantation of guide cannulas bilaterally into the Acb and recovery from surgery, the rats were microinjected with either the D1 antagonist SCH 23390 (0.1 to 2.0 micrograms/side), the D2 antagonist sulpiride (0.1 to 2.0 micrograms/side) or vehicle, and ethanol intake was monitored. The D1 antagonist SCH 23390 had little effect on alcohol intake although the 0.5 ug/side dose produced a small increase which was not statistically significant. The D2 antagonist sulpiride increased, in a dose dependent manner, the intake of ethanol to as high as 215% of control values (F(4,28) = 39.9; p < 0.001). Additional experiments indicated that the 2.0 micrograms/side dose of sulpiride did not alter the consumption of a 14% glucose nor a 0.25% saccharin solution. These data suggest that D2 receptors in the Acb are important in the regulation of alcohol drinking by the P line of rats.
Alcohol Drinking↗
Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.
The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2, ADH3*1, and ALDH2*2 alleles than did the nonalcoholics, suggesting that genetic variation in both ADH and ALDH, by modulating the rate of metabolism of ethanol and acetaldehyde, influences drinking behavior and the risk of developing alcoholism.
Alcohol Dehydrogenase↗
Higher density of serotonin-1A receptors in the hippocampus and cerebral cortex of alcohol-preferring P rats.
Saturable [3H]-8OHDPAT binding to 5HT-1A receptors in membranes prepared from hippocampus and frontal cerebral cortex of alcohol-preferring P rats and of alcohol-nonpreferring NP rats has been compared. The Bmax values or densities of recognition sites for 5HT-1A receptors in both brain areas of the P rats are 39 and 131 percent, respectively, higher than those in the NP rats. The corresponding KD values are 38 and 44 percent lower in the P rats than in the NP rats, indicating higher affinities of the recognition sites for the 5HT-1A receptors in hippocampus and cerebral cortex of the P rats. These findings indicate either an enrichment of 5HT-1A receptor density during selective breeding for alcohol preference or an upregulation of 5HT-1A receptors developed as an adaptation to lower presynaptic concentrations of 5HT found in these brain areas of P rats as compared with the NP rats.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference.
The effect of naloxone on voluntary ethanol intake was examined in rats which were selectively bred for oral ethanol preference (High Alcohol Drinking or HAD line). Rats of the HAD line were treated with naloxone in doses of 0.05-18.0 mg/kg b.wt. before access to water alone or to a free-choice between a 10% (v/v) ethanol solution and water. Naloxone suppressed water intake when water was presented as the sole source of fluid. In contrast, naloxone produced a dose-dependent decrease in ethanol consumption, without altering water intake, when rats were given a free-choice between the ethanol solution and water. Selective suppression of ethanol consumption by naloxone was not attributable to changes in blood ethanol concentrations or ethanol elimination rates following naloxone treatment. It appears that although naloxone may attenuate the positively reinforcing properties of both ethanol and water, ethanol drinking is a subset of consummatory behaviors that is particularly sensitive to opioid receptor blockade. The results suggest that activation of the endogenous opioid system may be an important mechanism which serves to maintain continued ethanol drinking.
Alcohol Drinking↗
Alcohol and aldehyde dehydrogenase.
The enzymes mainly responsible for ethanol degradation in humans are liver alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH). Polymorphisms occur in both enzymes, with marked differences in the steady-state kinetic constants. The Km-values for ethanol of ADH isoenzymes relevant for alcohol degradation range from 49 microM to 36 microM, and the Vmax-values from 0.6 to 10 U/mg. Expression of an inactive form of the ALDH2 isoenzyme, the so-called Oriental variant, results in impaired acetaldehyde metabolizing capacity. The differences in ethanol and acetaldehyde metabolizing activities of allelic enzyme forms may be responsible in part for the large variation in the alcohol metabolism rate in humans. Interindividual differences in the isoenzyme pattern may contribute to the genetically determined predisposition for excessive alcohol intake.
Alcohol Dehydrogenase↗
Increased number of GABAergic terminals in the nucleus accumbens is associated with alcohol preference in rats.
Ethanol is known to be anxiolytic and this effect may be mediated through GABA transmission acting on the GABAA-benzodiazepine-Cl- ionophore complex. Recent studies from our laboratory have suggested that GABA transmission and the GABAA-benzodiazepine-Cl- ionophore complex might be involved in the rewarding action of ethanol in alcohol-preferring rats. We report here immunocytochemical and morphometric studies analyzing the GABAergic terminal density in the nucleus accumbens (NA), corpus striatum, nucleus tractus solitarius, and lateral septum of the selectively bred P (alcohol-preferring) and the NP (alcohol-nonpreferring) lines of rats, as well as of the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines of rats. The NA was included for analysis because this structure has been implicated as an important component of the brain reward system. An increase of GABAergic terminal density was found in the NA of the P rats, when compared with the NP rats. Similarly, there were more GABAergic terminals in the NA of HAD rats than of the LAD rats. No differences between the lines were seen in the other brain regions examined. The results suggest that alcohol preference in P and HAD rats may be related to increased GABA terminals and enhanced GABAergic inhibition within the NA.
Alcohol Drinking↗
Purification and steady-state kinetic characterization of human liver beta 3 beta 3 alcohol dehydrogenase.
Human liver alcohol dehydrogenase catalyzes the NAD+-dependent oxidation of alcohols. Isoenzymes are produced in liver by five different genes, two of which are polymorphic. We have studied the three beta beta isoenzymes produced at ADH2 because they exhibit very different kinetic properties and they appear with different frequencies in different racial populations. The beta 3 beta 3 isoenzyme which appears in 25% of black Americans was purified to homogeneity, and conditions were found to stabilize this labile isoenzyme. The comparison of substrate specificity among beta beta isoenzymes for primary straight-chain alcohols indicates that there is a positive correlation between Vmax/KM and the log octanol/water partition coefficient for alcohols with beta 2 beta 2 and beta 3 beta 3 but not with beta 1 beta 1. Methyl substitutions at C1 or C2 of these alcohols reduce the catalytic efficiency with all three isoenzymes. The KM and Ki values of beta 3 beta 3 for NAD+ and NADH are substantially higher than values for beta 1 beta 1 or beta 2 beta 2. The Vmax of beta 3 beta 3 ethanol oxidation is 90 times that of beta 1 beta 1. Sequencing of the beta 3 subunit and gene indicates that the polymorphism results from a single amino acid exchange of Cys-369 in beta 3 for Arg-369 in beta 1 and beta 2 [Burnell et al. (1987) Biochem. Biophys. Res. Commun. 146, 1227-1233]. In horse alcohol dehydrogenase and beta 1 beta 1, the guanidino group of Arg-369 is thought to stabilize the NAD(H)-enzyme complex by bonding to one of the pyrophosphate oxygens.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Dehydrogenase↗
Stereospecific oxidation of secondary alcohols by human alcohol dehydrogenases.
The human liver alpha alpha alcohol dehydrogenase exhibits a different substrate specificity and stereospecificity for secondary alcohols than the human beta 1 beta 1, and gamma 1 gamma 1 or horse liver alcohol dehydrogenases. All of the enzymes efficiently oxidize primary alcohols, but alpha alpha oxidizes secondary alcohols far more efficiently than human beta 1 beta 1 and gamma 1 gamma 1 or horse liver alcohol dehydrogenase. Specifically, alpha alpha oxidizes four- and five-carbon secondary alcohols with efficiencies 0.06-2.2 times that of primary homologs and oxidizes these secondary alcohols with efficiencies up to 3 orders of magnitude greater than those of the three other isoenzymes. Whereas the human beta 1 beta 1, gamma 1 gamma 1 and horse isoenzymes show a distinct preference toward (S)-(+)-3-methyl-2-butanol, the alpha alpha isoenzyme prefers (R)-(-)-3-methyl-2-butanol. Computer-simulated graphics demonstrate that the horse subunit accommodates (S)-(+)-3-methyl-2-butanol within the active site much better than the opposite stereoisomer, primarily due to steric hindrance caused by Phe-93. Human alpha may accommodate (R)-(-)-3-methyl-2-butanol better than (S)-(+)-3-methyl-2-butanol because of close contacts between the latter and Thr-48. These observations suggest that substitutions at positions 93 and 48 in the active site of human liver alcohol dehydrogenase isoenzymes may determine their substrate specificity for secondary alcohols.
Alcohol Dehydrogenase↗