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T K Li

Publications and source records attributed to T K Li.

At least 217 records · Page 12Linked to original sources
PubMed1989

Serotonin and ethanol preference.

This chapter brings together evidence indicating the involvement of serotonin (5-HT) in ethanol preference using data mainly obtained from selectively bred alcohol-preferring and alcohol-nonpreferring lines of rodents. Although several laboratories have established rodent lines that will consume large quantities of ethanol daily, only one line thus far has been established that satisfied all the criteria for an animal model of alcoholism and that would be suitable for studying the biological basis of ethanol preference. This is the P line of alcohol-preferring rats that: (1) freely consumes 5-9 g ethanol/kg body wt/day; (2) drinks sufficient alcohol to produce intoxicating blood alcohol concentrations; (3) works to obtain alcohol; (4) self-administers ethanol for its CNS pharmacological effects; and (5) develops chronic tolerance to and dependence on alcohol with free-choice drinking. Relative to the NP line of alcohol-nonpreferring rats, the P rat has lower 5-HT levels in several CNS regions, including some, such as the nucleus accumbens, hypothalamus, and frontal cortex, which are involved in the brain reward circuitry. Furthermore, both acute and chronic ethanol administration have effects on the 5-HT pathway from the dorsal raphe nucleus to the nucleus accumbens in the P rat. Pharmacological studies have demonstrated that fluoxetine, a serotonin uptake inhibitor, reduced the oral consumption or intragastric self-administration of alcohol in the P rats. In addition, administration of a 5-HT1B agonist also attenuated the oral intake of ethanol by P rats. It is hypothesized that the serotonergic pathway from the dorsal raphe nucleus to the nucleus accumbens is involved in the reinforcing actions of alcohol in the P line of rats.

Alcohol Drinking↗
PubMed1989

Spiroxatrine augments fluoxetine-induced reduction of ethanol intake by the P line of rats.

The present study was undertaken to determine if spiroxatrine, a reported 5-HT1A antagonist, could block the attenuating effects of fluoxetine (a 5-HT uptake inhibitor) on voluntary ethanol intake by the selectively bred alcohol-preferring P line of rats. Fluoxetine (10 mg/kg, IP) significantly reduced the intake of 10% ethanol by P rats approximately 50% during the 4-hour period of alcohol availability. Spiroxatrine (4 mg/kg, IP) was without effect on ethanol intake when given alone. However, when given 5 minutes before fluoxetine (10 mg/kg, IP), this dose of spiroxatrine augmented the reduction of ethanol intake to approximately 15% of control values after 4 hours. Similar experiments conducted with 1 mg/kg (IP) 8-hydroxy-2(di-N-propylamino) tetralin (DPAT) demonstrated that this 5-HT1A agonist also enhanced the attenuating effects of fluoxetine on ethanol intake. Likewise, spiroxatrine augmented the DPAT reduction of alcohol intake. Spiroxatrine enhanced the effect of DPAT and fluoxetine on food intake as it did on ethanol intake. The results suggest that spiroxatrine behaved as a partial agonist and/or modulator and not as an antagonist at 5-HT1A receptors under the present experimental conditions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Autonomic and subjective responses to alcohol stimuli with appropriate control stimuli.

Previous studies on "craving" for alcohol after exposure to olfactory stimuli for alcohol may be criticized on the grounds that the control stimuli were not really appropriate. We included exposure to a preferred nonalcoholic beverage and to a sweet food item as additional control stimuli in order to better compare the salivary, autonomic, and self-reported craving responses of alcoholics with normal social drinkers. The results indicated that the salivation measure was differentially sensitive to the alcohol stimulus, even when compared to appropriate control stimuli. It is possible that self-reported craving is a biased measure in alcoholic inpatients in treatment.

Adult↗
PubMed1989

Ethanol reinforcement in the alcohol nonpreferring rat: initiation using behavioral techniques without food restriction.

Genetic selection of rats can markedly alter their ethanol consumption. The manner in which environmental factors interact in these genetically selected animals to influence ethanol consumption has not been thoroughly investigated. Using the alcohol-nonpreferring (NP) line of rats selectively bred at the Indiana University School of Medicine, alcohol self-administration in an operant situation was initiated using either a sucrose-fading or a secondary-conditioning procedure. These initiation procedures do not require any food or fluid restriction. Initiation was successful in 10 out of 12 NP animals, with the initiated rats self-administering ethanol at concentrations as high as 40%. Following initiation, a retest of home-cage ethanol preference found increases in ethanol acceptability. When tested in a concurrent operant situation, the initiated NP rats also chose ethanol over water. However, the NP rats had lower alcohol intakes and a different pattern of drinking over time when compared to that of nonselected Long-Evans rats. While the NP rats could be initiated to lever-press for ethanol, at no time did their intake approach that of the selected line of alcohol-preferring (P) rats. Thus, while an upward shift from the genetic baseline in ethanol preference and intake can result from the environmental initiation manipulations employed in these studies, genetic factors would appear to limit the extent to which ethanol ingestion can be increased.

Alcohol Drinking↗
PubMed1989

Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.

Many Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity responsible for the oxidation of acetaldehyde produced during ethanol metabolism. These individuals suffer the alcohol-flush reaction when they drink alcoholic beverages. The alcohol-flush reaction is the result of excessive acetaldehyde accumulation, and the unpleasant symptoms tend to reduce alcohol consumption. The subunit of this homotetrameric enzyme was sequenced and the abnormality in the inactive enzyme shown to be a substitution of lysine for glutamate at position 487. We have used the polymerase chain reaction to determine the genotypes of 24 livers from Japanese individuals. Correlating genotype with phenotype leads to the conclusion that the allele (ALDH2(2)) encoding the abnormal subunit is dominant.

Aldehyde Dehydrogenase↗
PubMed1988

Alcohol effects on the percentage of beta waves in the electroencephalograms of twins.

Electroencephalogram (EEG) recordings were made from 26 pairs of monozygotic (MZ) and 26 pairs of dizygotic (DZ) adult male twins, before and after alcohol ingestion. After a baseline EEG and a light breakfast, 1.2 ml/kg of ethanol was given orally over 15 min and the EEG repeated four times at hourly intervals. Alcohol caused a significant drop in the percentage of beta waves (14-30 cycles/sec) during the 1st hr. For the percentage of beta waves in 38 pairs of twins with complete data, MZ twin beta-wave intraclass correlations (RMZ) ranged between 0.85 and 0.91 before and after alcohol, but the DZ intraclass correlations (RDZ) started at 0.54 and fell to 0.05 at 2 hr after alcohol before recovering to baseline levels. These correlations resulted in heritability estimates [2(RMZ-RDZ)] of 0.68 at baseline and 1.73 at 2 hr. A heritability of 1.43 was found for the 1st hr drop in percentage of beta waves (RMZ = 0.78, RDZ = 0.06). These unrealistically high heritabilities, due to RDZ's approaching 0.0, suggest a failure of assumptions in the linear twin model that was used. Also, these findings are similar to, but more exaggerated than, findings in resting EEG's and visually evoked EEG potentials of twins and are compatible with the influence of gene interactions.

Adult↗
PubMed1988

Serotonergic and adrenergic receptors in alcohol-preferring and non-preferring rats.

Serotonergic and adrenergic receptors in brain areas of the alcohol-preferring P and alcohol-nonpreferring NP rats were compared by radioligand-binding assays. Binding of 3H-serotonin (3H-5HT) to 5HT-1 receptors in membranes of cerebral cortex and hippocampus was significantly higher in density (B max values) and affinity (Kd values) in the P than in the NP rats, whereas B max values in membranes from the brain stem of the P rats were lower than those of the NP rats. No significant difference between the P and NP lines was observed when the binding of 3H-ketanserin to 5HT-2 receptors and of 3H-WB4101, 3H-clonidine and 3H-dihydoalprenolol to alpha-1, alpha-2 and beta-adrenergic receptors was compared. The increase of 3H-5HT binding probably indicates up-regulation or supersensitivity of 5HT-1 receptors as a compensatory mechanism to the lower levels of 5HT in brain areas of the P rats (Murphy, et al., 1982).

Alcoholism↗
PubMed1988

Effects of Ro 15-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the alcohol-preferring (P) and -nonpreferring (NP) lines of rats.

The effects of the IP administration of RO 15-4513 (1, 2 and 4 mg/kg), fluoxetine (5 and 10 mg/kg) and desipramine (5 and 10 mg/kg) on the intake of 10% ethanol, H2O and food were determined in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats with daily access to fluids being limited to single 2-hour sessions. The imidazobenzodiazepine Ro 15-4513 (a partial inverse benzodiazepine agonist) significantly reduced the intake of 10% ethanol by the P rats to 50-60% of control levels in the first 30 minutes without altering food or H2O intake. The attenuating actions of 2 mg/kg Ro 15-4513 on ethanol intake could be completely blocked by the central benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg). Ro 15-1788, by itself, produced no effects on alcohol and H2O consumption. The 5 mg/kg dose of fluoxetine significantly reduced 10% ethanol intake by the P rats to 20% of control values without altering either H2O or food consumption. The 10 mg/kg dose of fluoxetine further reduced ethanol intake by the P rats, but this dose also reduced daily food intake to approximately 70% of normal. Desipramine at both doses significantly (p less than 0.05) reduced both ethanol and food uptake by the P rats and had a tendency to reduce H2O consumption as well. In general, the three drugs had effects in the NP rats similar to those observed for the P group, although the effects on 10% ethanol intake were difficult to compare because of the low, variable intake of alcohol by the NP group.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1988

Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats.

The contents of dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex, anterior striatum, nucleus accumbens and hypothalamus of alcohol-tolerant and -nontolerant rats of the alcohol-preferring P line were determined one hour after the IP administration of 2.5 g ethanol/kg body wt. Compared with saline-injected controls, nontolerant P-rats injected with ethanol had (a) 60% higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the frontal cortex; (b) 30-60% higher levels of DOPAC and HVA in the anterior striatum and nucleus accumbens; and (c) 20% higher levels of 5-HIAA in all three forebrain regions. In the tolerant group, the effects of IP ethanol on DOPAC and HVA were markedly attenuated or completely eliminated in these three forebrain regions. However, in the case of 5-HIAA, an attenuated response was observed only in the nucleus accumbens of the tolerant group. The IP administration of ethanol had little effect on the contents of DA or 5-HT in any of these three forebrain regions, with the exception that 5-HT levels were elevated in the anterior striatum of both the tolerant and nontolerant groups. In the hypothalamus, there were no significant differences for the contents of DA, 5-HT or their metabolites between the nontolerant or tolerant P rats after IP ethanol. The data indicate that both acute ethanol administration and chronic alcohol intake by the P line of rats alters certain DA and 5-HT systems that may be involved in the brain reward circuitry and in DA pathways involved in motor functions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Differences in response to the aversive properties of ethanol in rats selectively bred for oral ethanol preference.

A conditioned taste aversion (CTA) paradigm was used to determine whether aversion to the pharmacological effects of ethanol, apart from orosensory cues, can contribute to genetic differences in voluntary ethanol consumption. Four doses of ethanol, administered IP, were paired with the consumption of a 0.1% saccharin solution in rats from the alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Repeated pairing of saccharin and ethanol in a dose of 1.0 g/kg produced stronger and more prolonged aversion to saccharin in NP rats, compared with P rats, at comparable blood ethanol levels. A low dose of ethanol (0.25 g/kg) produced transient conditioned facilitation of saccharin consumption in P rats, but not in NP rats, at comparable blood ethanol levels. The results suggest that rats of the NP line find the postingestional effects of high-dose ethanol more aversive, and low-dose ethanol less reinforcing, than do rats of the P line. Genetic differences in voluntary ethanol consumption may be due, in part, to differences in aversion to the postingestional effects of ethanol.

Alcohol Drinking↗
PubMed1988

Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease.

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.

Alcohol Dehydrogenase↗
PubMed1988

Effect of low dose ethanol on the EEG of alcohol-preferring and -nonpreferring rats.

Low dose ethanol has been shown to differentially affect the behavior of alcohol-preferring (P) and -nonpreferring (NP) rats. The present study was undertaken to determine if this differential effect is reflected in the EEG of these two rat lines. Frontocortical and hippocampal EEG were recorded from P and NP rats after intragastric infusions of ethanol (0.5 g/kg) and vehicle. Spectra were created from sequential 8-second epochs and power was calculated for frequency bands 0-4, 4-8, 8-16 and 16-50 Hz. Band power data was then grouped according to the rat's behavior and compared for P and NP rats. During nonREM sleep, ethanol produced a persistent increase in power in the NP rats, while power in the P rats was initially decreased, then returned to baseline. This differential effect was seen at both recording sites. The results suggest the P rats were midly aroused by low dose ethanol, while the NP rats were mildly sedated.

Alcohol Drinking↗
PubMed1988

Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3 loci following DNA sequence amplification.

Humans are polymorphic at two of the alcohol dehydrogenase (ADH) loci important in ethanol metabolism, ADH2 and ADH3. Although the coding regions of these genes are 94% identical, they produce subunits that differ greatly in kinetic properties in vitro. These differences are likely to be reflected in the pharmacokinetics of alcohol metabolism, but studies have been hampered by the need to use liver biopsy specimens to determine the ADH phenotype. This problem has now been overcome by determining the genotype at these loci using DNA that has been amplified in vitro by the polymerase chain reaction. We report here the identification of all three of the ADH2 alleles and both of the ADH3 alleles. Any pair of ADH2 or ADH3 alleles can be distinguished using allele-specific oligonucleotide probes directed at their single base pair difference. In addition, ADH2(2) can be distinguished from ADH2(1) and ADH2(3) by detecting a new MaeIII site created in the third exon by the single base pair alteration in ADH2(2).

Alcohol Dehydrogenase↗
PubMed1988

Pharmacology of alcohol preference in rodents.

In alcoholism research, two fundamental and closely related questions are: "Why do people drink?" and "Why do some people drink too much?" Humans voluntarily drink alcoholic beverages or self-administer alcohol, more often than not, in a social setting. Environmental factors and how individuals react to them can, therefore, have powerful influences on drinking behavior. On the other hand, the neuropsychopharmacological actions of ethanol and how different individuals react to them can be important biological determinants. Ethanol's action is biphasic, i.e., it can be reinforcing (rewarding) in the low concentration range, but aversive at high concentrations. Perception by the individual of the reinforcing actions of ethanol might be expected to maintain alcohol-seeking behavior, whereas aversive effects would be expected to extinguish this behavior. Identification of the environmental and biological variables that promote and maintain alcohol-seeking or alcohol self-administration behavior is key to our understanding of the disorder alcoholism itself.

Alcoholism↗
PubMed1987

The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding.

The beta 3 beta 3 (formerly called beta Indianapolis) and beta 1 beta 1 isoenzymes of human alcohol dehydrogenase differ substantially in their catalytic properties. Specifically, the KM value for NAD+ of beta 3 beta 3 is 70 times greater than that of beta 1 beta 1, and the Ki value for NADH is 35 times greater than that of beta 1 beta 1. To identify the structural basis of these catalytic differences, we sequenced regions of the beta 3 subunit and the beta 3 gene. beta 3 differs from beta 1 by the substitution of Cys for Arg-369. Based on x-ray crystallography of horse ADH, Arg-369 should interact with the nicotinamide phosphate moiety of NAD(H). The Cys for Arg-369 substitution would decrease the enzyme's affinity for coenzyme and, thus, account for the observed kinetic differences between beta 3 beta 3 and beta 1 beta 1.

Alcohol Dehydrogenase↗
PubMed1987

Purification and characterization of the Danish (Skive) variant of mouse liver alcohol dehydrogenase.

The partially inbred Danish (Skive) strain of mice exhibits a form of liver alcohol dehydrogenase (ADH) which differs in electrophoretic mobility from that of all other inbred mouse strains thus far examined, e.g., C57BL/10, DBA/2J, and BALB/c. In order to compare the catalytic and molecular properties of the "variant" and "normal" enzyme forms, they were purified to homogeneity by ion-exchange and affinity chromatography. Tryptic peptides of reduced and carboxymethylated subunits of the normal and variant ADH forms were mapped by thin-layer two-dimensional electrophoresis and chromatography and by reversed-phase high-performance liquid chromatography. A unique nonapeptide in the Danish mouse liver ADH which did not appear in enzymes from C57BL/10, DBA/2J, or BALB/c mice was identified by both methods. Amino acid sequencing of this peptide revealed that the Arg residue at position 124, as predicted from the cDNA sequence of ADH in DBA/2J mice, has been replaced by Leu in the Danish variant. The Leu for Arg substitution in the variant form appears to account for its decreased cathodic mobility with electrophoresis in starch gels at pH 7.2. The Km and Vmax of ADH from the Danish strain for three primary alcohols and three aldehydes were similar in value to those of ADH from the C57BL/10, DBA/2J, and BALB/c strains. Based on the X-ray structure of horse liver ADH, position 124 is on the solvent-exposed surface of the catalytic domain. The finding that the kinetic constants are similar for the normal and variant forms is consistent with the observation that this residue is not in the active site and that there is no known role for it in the ADH catalytic mechanism.

Alcohol Dehydrogenase↗