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T K Li

Publications and source records attributed to T K Li.

At least 181 records · Page 10Linked to original sources
PubMed1993

Effects of oral ethanol self-administration on the EEG of alcohol preferring and -nonpreferring rats.

EEG measures have been shown to differ in human subjects who are at genetically increased risk for the development of alcoholism. In the present study, EEG was recorded in rats that were selectively bred for alcohol-preferring (P) and nonpreferring (NP) behaviors during an ethanol self-administration paradigm. In this paradigm, rats initially learned to press a lever for a 0.2% saccharin solution. Ethanol was then added to the saccharin solution in increasing concentrations while saccharin was faded progressively. EEG recordings were analyzed under three different conditions: baseline, 0.2% saccharin and 10% ethanol. Statistical analyses were carried out within each group of rats for three 10-min intervals in each condition. NP rats showed increases in EEG power in the 6-32 Hz frequency ranges 20-30 min following ethanol availability. In contrast, no significant EEG effects were found for P rats in the 10% ethanol condition with respect to time. EEG power in the three time periods (0-10, 10-20, 20-30 min) was also compared between conditions (baseline, saccharin, 10% ethanol). For NP rats, a significant increase in EEG power during the 20-30 min time interval was found in the 10% ethanol session for the 16-32 Hz frequency range as compared to baseline and saccharin. In P rats, a significant increase in the power of the EEG was found during the first 10 min in the 10% ethanol session in the 8-16 Hz frequency range as compared to baseline and saccharin. The two rat lines also differed in their behavioral responses to the self-administration paradigm.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1993

Mitochondrial aldehyde dehydrogenase (ALDH2) polymorphism in AA and ANA rats: lack of genotype and phenotype line differences.

Polymorphism of the gene coding for mitochondrial ALDH2 in humans is known to be associated with differences in alcohol drinking behavior. Recently, two different alleles of the ALDH2 gene, ALDH2R and ALDH2Q, have been found in rats also and a possible relationship between the frequencies of the two alleles and drinking behavior has been proposed. In this study, we examined whether this polymorphism of ALDH2 was the underlying cause for the previously reported acetaldehyde accumulation in the alcohol-avoiding ANA rat line and, thus, could be one of the factors explaining the differences in alcohol drinking behavior between the ANA and the alcohol-preferring AA rat lines. The experimental animals were genotyped and their mitochondrial ALDH activities and blood acetaldehyde concentrations after ethanol injection were measured. The two lines did not differ in their frequencies of ALDH2R and ALDH2Q alleles. Thus, the polymorphism in the ALDH2 gene does not explain the acetaldehyde accumulation in ANA rats and it does not seem to be associated with differences in the alcohol drinking behavior in these rat lines.

Acetaldehyde↗
PubMed1993

Greater abundance of serotonin1A receptor in some brain areas of alcohol-preferring (P) rats compared to nonpreferring (NP) rats.

Saturable [3H]8-OHDPAT binding to recognition sites of 5-HT1A receptors was shown to be higher in cortical membranes of alcohol-preferring (P) than in membranes of alcohol-nonpreferring (NP) rats. Neither the P nor the NP lines had been previously exposed to ethanol. The increase in binding was mainly due to 40-56% higher density or maximum of binding sites (Bmax) without significant change in affinity or dissociation constant (Kd) for the radioligand. Although Bmax values were also consistently higher in membranes isolated from other brain areas of P rats, including hypothalamus, striatum, and hippocampus, the differences did not reach statistical significance. Similar to the previously reported lack of difference in [3H]ketanserin binding to 5-HT2 receptors in cortical membranes from P and NP rats, there were also no significant differences in saturable binding of [3H]mesulergine and [3H]LY278584 to recognition sites of 5-HT1C and 5-HT3 receptors, respectively. Thus, an upregulation of 5-HT1A receptors in cerebral cortex and possibly in other brain areas of ethanol-naive P rats appears to have occurred as a consequence of the lower 5-HT innervation in this selected line of rats (13,15,27,28).

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Serotonin-2 receptors in the CNS of alcohol-preferring and -nonpreferring rats.

The densities of serotonin-2 (5-HT2) receptors, labelled with [3H]ketanserin (Ket), were examined in the CNS of alcohol-naive, adult, male alcohol-preferring (P) and -nonpreferring (NP) rats using quantitative autoradiography. The densities of binding sites labelled with 2.0 nM [3H]Ket were 15-25% lower (p < 0.05) in layer IV of the medial prefrontal, frontal, cingulate, parietal, and temporal cortices of the P line compared with the NP line. [3H]Ket binding in the P rats was also 40-50% lower (p < 0.05) in the medial and lateral nucleus accumbens, olfactory tubercle, and caudate-putamen, and 20% lower (p < 0.05) in the claustrum, compared with the NP line. No differences in 2.0 nM [3H]Ket binding were observed between the lines in the piriform cortex, hypothalamus, amygdala, hippocampus, ventral tegmental area, substantia nigra, central gray, and interpenduncular nucleus. Scatchard analysis of [3H]Ket binding (0.5-0.6 nM, determined in layer IV of the frontal and parietal cortex and in the lateral nucleus accumbens, indicated lower Bmax values without a change in Kd for the P compared to the NP rats. The results of this study indicate that there are fewer 5-HT2 receptors in certain CNS regions of the P relative to the NP rats.

Alcohol Drinking↗
PubMed1993

Housing conditions alter GABAA receptor of alcohol-preferring and -nonpreferring rats.

The effects of housing conditions on some functional properties of the GABAA benzodiazepine (BZD) receptor in the cerebral cortex were examined in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats. Compared to rats housed in pairs (P with P and NP with NP), P and NP rats housed individually had 44% (p < 0.005) and 32% (p < 0.01) lower values, respectively, for GABA-stimulated 36Cl- influx into cortical microsacs. The maximal effect (Vmax) of flunitrazepam (FNZ) to enhance GABA-stimulated 36Cl- uptake was 44% higher in individually housed P rats than pair-housed P rats (p < 0.05) and 51% higher than individually housed NP rats (p < 0.05). There was no difference between single and pair-housed NP rats for Vmax values of FNZ enhancement of GABA-stimulated 36Cl- influx. The results show housing conditions can alter some of the functional properties of the GABAA/BZD receptor in the P and NP lines of rats. The differential effect of housing conditions on FNZ enhancement of 36Cl- influx, observed between the lines, may be a result of higher levels of anxiety being produced by brief isolation in the P rat.

Alcohol Drinking↗
PubMed1993

Alcohol-preferring and nonpreferring rats display different levels of neurofilament proteins in the ventral tegmental area.

Previously, different levels of neurofilaments (NF) in the ventral tegmental area (VTA) have been identified in Sprague-Dawley rats treated chronically with morphine or cocaine and in drug-naive Lewis and Fischer 344, inbred strains that differ behaviorally in several ways, including alcohol, opiate, and cocaine preferences. These findings led us to examine whether rat lines that have been selectively bred for a difference in alcohol preference, the alcohol-preferring (P) and nonpreferring (NP) rats, also express different levels of NFs in the VTA. We found by use of back phosphorylation and immunolabeling procedures that the VTA of the P rat contains 20-50% lower levels of the three major types of NF proteins--NF-200, NF-160, and NF-68--compared with the VTA of the NP rat. No strain difference in NF levels was seen in the substantia nigra (which like the VTA is a major dopaminergic nucleus in brain), locus coeruleus (which is a major noradrenergic nucleus in brain), or spinal cord (which is enriched in NF proteins). In contrast to NFs, no P-NP line differences were found in VTA levels of tyrosine hydroxylase, which is also regulated by chronic morphine and cocaine treatments in Sprague-Dawley rats and shows prominent Lewis-Fischer strain differences, specifically in this brain region. The results provide additional support for the possibility that levels of NFs in the VTA may be related to preference for alcohol and other drugs of abuse.

Alcoholism↗
PubMed1993

Purification and partial amino acid sequence of a high-activity human stomach alcohol dehydrogenase.

To understand the relative importance of alcohol dehydrogenase (ADH) isoenzymes in gastric ethanol metabolism, a stomach-specific ADH (sigma-ADH) was purified to homogeneity from human transplant donor and surgical tissues, and its activity for ethanol oxidation was examined. The enzyme from these tissues had a specific activity at pH 10 of approximately 70 units/mg, about 10 times that reported by Moreno and Parés (J. Biol. Chem. 266:1128-1133, 1991). The enzyme exhibited a high Km for ethanol at pH 7.5 and 10 (29 and 5.2 mM, respectively). This high-activity sigma-ADH isoenzyme migrated on starch and isoelectric focusing gels to a position slightly anodic to the liver pi pi isoenzyme. It was subjected to digestion by endoproteinases, and approximately 40% of the protein was sequenced. The sigma-ADH exhibited 75%, 68%, and 62% sequence identity to the human class I (beta 1), II (pi), and III (chi) isoenzymes, respectively, and 61% identity to the deduced ADH6 amino acid sequence. Phylogenetic analysis indicated that precursors to this high-activity sigma-ADH and the class I isoenzymes diverged more recently than precursors to the class II and III isoenzymes, after reptilian and avian divergence. The high-activity sigma-ADH isoenzyme therefore represents a distinct class of ADH (class IV), more closely related in evolution to the class I isoenzymes than to the other known human isoenzymes.

Adult↗
PubMed1993

An experimental approach to understanding the genetic and neurobiological basis of alcoholism.

The development and characterization of an animal model to study mechanisms underlying abnormal alcohol-seeking behavior have been described. Raised by genetic means, it demonstrates the importance of genetic factors in this behavior. It has allowed the elucidation of neural pathways and neurotransmitter systems that subserve alcohol-seeking behavior. It offers the potential for screening new medications for the treatment of alcoholism, based upon these kinds of newly discovered knowledge.

Alcohol Drinking↗
PubMed1993

CNS mechanisms of alcohol self-administration.

Neurochemical and neuropharmacological studies were undertaken to examine the possible involvement of the ventral tegmental area (VTA) dopamine (DA) system and the dorsal raphe nucleus (DRN) serotonin (5-HT) system in regulating oral alcohol self-administration. In vivo microdialysis studies demonstrated that either i.p. ethanol administration (1.0-2.0 g/kg) or local perfusion with ethanol (100 mM) could enhance the extracellular concentrations of both DA and 5-HT in the nucleus accumbens (ACB). Furthermore, the effects of local perfusion with ethanol on DA release in the ACB could be blocked by co-perfusion with a 5-HT3 antagonist. In the selectively-bred alcohol preferring P line of rats, there appears to be abnormal 5-HT and/or DA systems in certain limbic structures, i.e., ACB, olfactory tubercles (OTU) and medial prefrontal cortex (MPF). This is indicated by (a) lower contents of DA and 5-HT; (b) fewer 5-HT immunostained fibers; (c) lower densities of 5-HT1B, 5-HT2 and D2 receptors; and (d) higher densities of 5-HT1A receptors in the CNS of P rats compared to the alcohol-nonpreferring NP line of rats. Neuropharmacological studies demonstrated that local microinfusion of the D2 antagonist, sulpiride, or, at low doses, the DA releaser, d-amphetamine, could increase alcohol drinking by P rats. Intracranial self-administration (ICSA) studies showed that the P line of rats, but not the NP line, will self-administer 50-150 mg% ethanol directly into the VTA. Overall, these results suggest an innate abnormal functioning of the VTA DA and DRN 5-HT systems may be key factors facilitating the rewarding actions of ethanol in the CNS of P rats.

Alcohol Drinking↗
PubMed1993

Recent developments in alcoholism:opioid peptides.

A large body of evidence indicates that the endogenous opioid system plays an important role in maintaining alcohol drinking behavior. Research is reviewed indicating that the reinforcing properties of alcohol which lead to continued and repeated bouts of drinking are due, in part, to alcohol-induced activation of the endogenous opioid system. Opioid receptor antagonists decrease alcohol craving, alcohol consumption, and loss of control over drinking. The potential of opioid receptor antagonists to improve treatment outcome in comprehensive relapse prevention programs is discussed.

Alcohol Drinking↗
PubMed1992

Corticotropin releasing factor (CRF): studies in alcohol preferring and non-preferring rats.

Electroencephalographic (EEG) responses to corticotropin releasing factor (CRF) as well as CRF concentrations in several brain regions were measured in two lines of rats which have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Fifteen rats were implanted with chronic electrodes and EEG spectra were evaluated following intracerebroventricular (ICV) administration of CRF (0.15 nmol) or saline. P rats demonstrated a significantly increased EEG response to CRF in the theta frequency range (ANOVA: PREF x DRUG 4-6 Hz, P less than 0.03; 6-8 Hz, P less than 0.05) in frontal cortex. A significantly lower concentration of CRF was found in the P rats in hypothalamus (P less than 0.02), amygdala (P less than 0.003), prefrontal cortex (P less than 0.01), and cingulate cortex (P less than 0.02). The finding that P rats had an increased response to exogenously administered CRF, taken together with decreased CRF concentrations, suggests that CRF receptors may be up-regulated in these animals. Differences in the regulation of CRF neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.

Alcohol Drinking↗
PubMed1992

Differences in the hypothermic response to ethanol in rats selectively bred for oral ethanol preference and nonpreference.

The duration of retention of tolerance to ethanol was tested in the alcohol-preferring (P) and alcohol-nonpreferring (NP) rats lines, using ethanol-induced hypothermia as a measure of tolerance. Rats received two injections of ethanol (3.5 g/kg) body wt, IP) and the time between the injections was 1, 2, or 3 days. When one day separated the two injections, tolerance to the hypothermic effect of a second "test" injection was found in both lines. When 2 or 3 days separated the two injections, the P line showed a loss of tolerance and the NP line showed sensitization to ethanol. Sensitization in the NP line grew stronger when the interval between injections was increased from 2 to 3 days. The duration of retention of tolerance to ethanol-induced hypothermia in the P line was shorter than has previously been reported for motor impairment in this line. It appears that the duration of tolerance retention in the P line depends on the test used to measure tolerance. Sensitization to ethanol in the NP line may be associated with low oral ethanol intake.

Alcohol Drinking↗
PubMed1992

Alcohol self-administration in a nonrestricted access situation with alcohol-preferring (P) rats.

Genetic variables have been implicated as contributing factors in the development of alcoholic behavior. Rats bred selectively for alcohol preference have been used in laboratory studies to investigate the role of such variables. In the present study, rats from the alcohol preferring (P) line were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. Food pellets (45 mg) were presented on an FR 1 schedule of reinforcement, while ethanol was presented in a 0.1 ml dipper on an FR 4 schedule of reinforcement. Water was available in a drinking tube with licks monitored by a drinkometer. Data were analyzed in terms of both total daily intakes and computer defined bouts. The P rats showed greater daily ethanol intakes compared with Long-Evans (LE) animals previously studied under similar access conditions. The major difference in intake was a result of the P rats having a greater number of daily ethanol drinking bouts, while having only a slight increase in individual bout size. These data indicate that genetic selection for ethanol preference may result in the regulation of ethanol intake by means of changes in the frequency of ethanol drinking bouts but not by changes in bout size.

Alcohol Drinking↗
PubMed1992

Ethanol enhances the release of dopamine and serotonin in the nucleus accumbens of HAD and LAD lines of rats.

The effects of intraperitoneal administration of ethanol, 0.5, 1.0, and 2.0 g/kg body weight, on the extracellular concentrations of dopamine (DA), serotonin (5-HT), and their major metabolites were studied in the nucleus accumbens (ACC) of alcohol-naive, selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines of rats using the technique of microdialysis. In both lines, the extracellular levels of DA were increased following the injection of 1.0 and 2.0 g of ethanol/kg body weight while only the 2.0-g/kg dose elevated the concentration of 5-HT. None of the ethanol doses altered the extracellular levels of the major metabolites of DA and 5-HT. Dose-response curves for DA and 5-HT release indicated no marked difference in the sensitivity to ethanol between the lines. Local perfusion with 60 mM K+ through the microdialysis probe markedly enhanced the release of DA and 5-HT in the ACC of both lines; there was a small difference between the lines in the amounts of DA, but not 5-HT, released by K(+)-stimulation. Overall, the results indicate that (1) the ACC DA system is more sensitive than the ACC 5-HT system to intraperitoneal ethanol administration in both lines and (2) there is no evidence for a relationship between alcohol preference and sensitivity of the ACC DA and 5-HT systems to acute intraperitoneal ethanol administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage.

Little is known about factors determining individual susceptibility to the physical complications of alcohol abuse but genetically determined differences in ethanol metabolism may be important. The oxidative metabolism of alcohol is catalyzed by alcohol and aldehyde dehydrogenase. Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three beta subunits) and ADH3 (producing two tau subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2. We have compared ADH2, ADH3 and ALDH2 allele frequencies in patients with alcohol-related cirrhosis (n = 59) and chronic pancreatitis (n = 13) with 79 local healthy control subjects. The different alleles were detected with allele-specific oligonucleotide probes after amplification of leukocyte DNA by the polymerase chain reaction. All patients and all but one control subject were homozygous ADH2*1, encoding the beta 1 subunit. No ADH2*3 alleles were detected. All 34 patients and 39 control subjects tested were homozygous ALDH2*1 encoding the active enzyme. ADH3 allele frequencies were different in patients and control subjects. ADH3*1 frequency: control subjects, 55.1%; cirrhotic patients, 62.7%; chronic pancreatitis patients, 65.4%. The difference between the patient groups combined and the control subjects was significant (p less than 0.05; G-test of Sokal and Rohlf) if it was assumed that the allele frequency in our control population was a reasonable estimate of our local population allele frequency. These results suggest that genetically determined differences in alcohol metabolism may, in part, explain predisposition to alcohol-related end-organ damage.

Alcohol Dehydrogenase↗