Biomedical subjects

T K Li

Publications and source records attributed to T K Li.

At least 91 records · Page 5Linked to original sources

PubMed1999

Involvement of the cyclic AMP-responsive element binding protein gene transcription factor in genetic preference for alcohol drinking behavior.

BACKGROUND: Cyclic adenosine 3',5'-monophosphate (cAMP)-responsive element binding (CREB) protein is a gene transcription factor that can integrate the signals mediated via the cAMP second messenger cascade at the gene expression level, which then controls neuronal functions. METHODS: To examine if the protein kinase A --> CREB signaling cascade is involved in genetic alcohol drinking preference, different measures of CREB were determined in various brain structures of alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. RESULTS: We show here that CRE-DNA binding activity is significantly decreased in the amygdala but not in the cortex, hippocampus, or striatum of P rats compared with NP rats. The levels of total CREB and phosphorylated CREB protein in the amygdala are significantly lower in P rats compared with NP rats. On the other hand, levels of the alpha-isoform of the catalytic subunit of protein kinase A protein, and basal as well as cAMP-stimulated protein kinase A activity are similar in the amygdala of both P and NP rats. CONCLUSIONS: Because P and NP rats are genetically bred for high and low alcohol drinking behavior, respectively, these results suggest the possibility that decreased expression of CREB protein in the amygdala may be associated with the high alcohol drinking behavior of P rats.

Activating Transcription Factor 2↗

PubMed1999

Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele.

BACKGROUND: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. METHODS: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. RESULTS: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. CONCLUSIONS: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

Adolescent↗

PubMed1999

Voluntary ethanol drinking during the first three postnatal weeks in lines of rats selectively bred for divergent ethanol preference.

BACKGROUND: Using a procedure first developed by Hall (1979), we examined ethanol self-administration in preweanling pups from Wistar rats and in lines of rats selectively bred for divergent ethanol preference (alcohol-preferring P, alcohol-nonpreferring NP, high-alcohol-drinking HAD-1 and -2, and low-alcohol-drinking LAD-2) to determine if factors contributing to high and low alcohol intakes are present early in development. METHODS: From postnatal days 5 to 20, nondeprived male and female rat pups received 30 min daily access to either water or a 15% (v/v) ethanol solution. In each daily session, pups were placed in a heated chamber containing Kimwipes soaked with a water or ethanol solution. Pups were weighed before and after each session, and intake levels were calculated as a percentage of body weight change. RESULTS: Similar to previous reports, Wistar pups exhibited over a 2-fold higher level of ethanol ingestion than water on postnatal days 9 through 14, with ethanol intakes approaching 3 g/kg body weight. When the drinking patterns of the selected lines were examined, only the HAD replicate lines showed a comparable preference for ethanol versus water during the preweanling period. The ethanol consumption of P, NP, and LAD lines was not consistently distinguishable from water intake levels. To reveal whether early ethanol exposure would influence later ethanol drinking behavior, a subset of HAD and LAD rat pups received free-choice ethanol access upon weaning. Although the divergent ethanol preference between high- and low-alcohol-drinking lines was evident within the first 4 days of access (>4 g/kg/day for HAD; <2 g/kg/day for LAD), preweanling ethanol exposure did not alter the acquisition or maintenance of ethanol drinking in either line. CONCLUSIONS: Overall, these results suggest that (a) the enhanced ethanol ingestion observed during the middle portion of the preweanling period is a robust phenomenon and generalizes across nonselected strains of rats, (b) selective breeding for divergent alcohol preference has arrested this age-specific effect in all but the HAD lines of rats, and (c) early ethanol exposure does not alter genetic dispositions for later high or low alcohol preference.

Alcohol Drinking↗

PubMed1999

Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians.

There is a functional polymorphism of the mitochondrial aldehyde dehydrogenase (ALDH2) gene with the variant allele (ALDH2*2) encoding a protein subunit that confers low activity to the tetrameric enzyme. Genetic epidemiologic studies have strongly suggested that homozygosity for the allele ALDH2*2 is sufficient in completely inhibiting the development of alcoholism in Asians. To study the pathophysiology of this unique pharmacogenetic effect, we recruited a total of eighteen adult Han Chinese men, matched by age, body-mass index, nutritional state and homozygosity at the alcohol dehydrogenase gene loci from a population base of 273 men. Six individuals were chosen for each of the three ALDH2 allelotypes: homozygous ALDH2*2/*2, heterozygous ALDH2*1/*2, and homozygous ALDH2*1/*1. Following a low dose of ethanol (0.2 g/kg body weight), blood ethanol/acetaldehyde concentrations, cardiac and extracranial/intracranial arterial hemodynamic parameters, as well as self-rated subjective sensations, were measured for 130 min. Homozygous ALDH2*2 individuals were found to be strikingly responsive to the small amount of alcohol, as evidenced by the pronounced cardiovascular hemodynamic effects as well as subjective perception of general discomfort for as long as 2 h following ingestion. This low-dose alcohol hypersensitivity, accompanied by a prolonged and large accumulation of acetaldehyde in blood, provides an explanation for the strong protection against heavy drinking and alcoholism in individuals homozygous for the ALDH2*2 gene allele.

Acetaldehyde↗

PubMed1998

Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells.

Protoberberines are a new class of organic cations that are dual poisons of topoisomerases I and II. Certain protoberberines exhibit greater in vitro cytotoxicity against cell lines derived from solid tumors than from leukemias. Using a group of seventeen different protoberberine analogs, the structural basis for selective cytotoxicity toward sensitive SF-268 glioblastoma cells as compared with resistant RPMI 8402 lymphoblast cells was explored. The selective cytotoxicity is associated with the presence of an imminium ion and other structural features of protoberberines, and is not shared by drugs such as camptothecin, doxorubicin, vinblastine, and etoposide, which are either equally or more cytotoxic against RPMI 8402 cells than SF-268 cells. The selective cytotoxicity of protoberberines against SF-268 over RPMI 8402 cells is not due to differences in topoisomerase levels or known drug efflux systems such as multidrug resistance (MDR1) and multidrug-resistance protein (MRP). Comparative in vitro studies of the accumulation of coralyne, a fluorescent protoberberine, into sensitive and resistant cells demonstrated a correlation between drug accumulation and selective cytotoxicity. Inhibitors of coralyne uptake included several protoberberine-related compounds. Of these, palmatine, a minimally cytotoxic protoberberine, both inhibited coralyne accumulation and reduced cytotoxicity against SF-268 cells, but not against RPMI 8402 cells. Despite the structural resemblance of protoberberines to catecholamines, our experiments using inhibitors and cells expressing biogenic amine uptake systems have ruled out the involvement of biogenic amine uptake1, uptake2, and vesicular monoamine transport systems. Uptake systems remaining as candidates, supported by preliminary data, include transport via vesicles derived from specialized membrane invaginations and selected carrier-mediated organic amine transport systems.

Antineoplastic Agents↗

PubMed1998

Effect of cellular retinol-binding protein on retinol oxidation by human class IV retinol/alcohol dehydrogenase and inhibition by ethanol.

All-trans retinoic acid (atRA) is a powerful morphogen synthesized in a variety of tissues. Oxidation of all-trans retinol to all-trans retinal determines the overall rate of atRA biosynthesis. This reaction is catalyzed by multiple dehydrogenases in vitro. In the cells, most all-trans retinol is bound to cellular retinol binding protein (CRBP). Whether retinoic acid is produced from the free or CRBP-bound retinol in vivo is not known. The current study investigated whether human medium-chain alcohol/retinol dehydrogenases (ADH) can oxidize the CRBP-bound retinol. The results of this study suggest that retinol bound to CRBP cannot be channeled to the active site of ADH. Thus, the contribution of ADH isozymes to retinoic acid biosynthesis will depend on the amount of free retinol in each cell. Physiological levels of ethanol will substantially inhibit the oxidation of free retinol by human ADHs: class I, alpha alpha and beta 2 beta 2; class II, pi pi; and class IV, sigma sigma.

Alcohol Oxidoreductases↗

PubMed1998

Anxiety proneness linked to epistatic loci in genome scan of human personality traits.

A genome-wide scan between normal human personality traits and a set of genetic markers at an average interval of 13 centimorgans was carried out in 758 pairs of siblings in 177 nuclear families of alcoholics. Personality traits were measured by the Tridimensional Personality Questionnaire. We detected significant linkage between the trait Harm Avoidance, a measure of anxiety proneness, and a locus on chromosome 8p21-23 that explained 38% of the trait variance. There was significant evidence of epistasis between the locus on 8p and others on chromosomes 18p, 20p, and 21q. These oligogenic interactions explained most of the variance in Harm Avoidance. There was suggestive evidence of epistasis in other personality traits. These results confirm the important influence of epistasis on human personality suggested by twin and adoption studies.

Anxiety↗

PubMed1998

Enhanced sensitivity of the nucleus accumbens proenkephalin system to alcohol in rats selectively bred for alcohol preference.

Evidence suggests that alcohol-induced activation of the endogenous opioid system is part of a neurobiological mechanism that may be functionally involved in alcohol reinforcement and high alcohol drinking behavior. We postulate that a genetic predisposition toward alcohol drinking is accompanied by increased responsiveness of the opioid system to alcohol. To test this hypothesis, the present study compared the effect of an acute alcohol challenge on enkephalin gene expression in discrete brain regions which are high in preproenkephalin (PPENK) mRNA content and/or are important in mediating alcohol reward in rats selectively bred for alcohol preference (P) or nonpreference (NP). PPENK mRNA content was measured by in situ hybridization performed with a 36 base oligonucleotide probe for PPENK mRNA and was quantified using a computerized image-analysis system. Blood alcohol concentration (BAC) and rate of alcohol elimination following alcohol infusion were similar in P and NP rats. P and NP rats did not differ in basal content of PPENK mRNA in any of the brain areas examined prior to onset of infusion. An intragastric (I.G.) infusion of alcohol (2.5 g/kg b.wt) produced a significant increase in PPENK mRNA in the nucleus accumbens (both shell and core) of P but not NP rats at 1 h after the onset of infusion which coincided with the time at which peak BAC was attained. In contrast, at 8 h after the onset of the alcohol infusion, when BAC was falling toward baseline, PPENK mRNA was decreased in the nucleus accumbens of both P and NP rats and in the anterior striatum and amygdala of NP rats. The results suggest that enhanced responsiveness of the enkephalinergic system to alcohol is associated with, and may be functionally involved in, mediating high alcohol drinking behavior.

Alcohol Drinking↗

PubMed1998

Genome-wide search for genes affecting the risk for alcohol dependence.

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Adolescent↗

PubMed1998

DNA minor groove binding-directed poisoning of human DNA topoisomerase I by terbenzimidazoles.

We have employed a broad range of spectroscopic, calorimetric, DNA cleavage, and DNA winding/unwinding measurements to characterize the DNA binding and topoisomerase I (TOP1) poisoning properties of three terbenzimidazole analogues, 5-phenylterbenzimidazole (5PTB), terbenzimidazole (TB), and 5-(naphthyl[2,3-d]imidazo-2-yl)bibenzimidazole (5NIBB), which differ with respect to the substitutions at their C5 and/or C6 positions. Our results reveal the following significant features. (i) The overall extent to which the three terbenzimidazole analogues poison human TOP1 follows the hierarchy 5PTB > TB >> 5NIBB. (ii) The impact of the three terbenzimidazole analogues on the superhelical state of plasmid DNA depends on the [total ligand] to [base pair] ratio (rbp), having no effect on DNA superhelicity at rbp ratios < or = 0.1, while weakly unwinding DNA at rbp ratios > 0.1. This weak DNA unwinding activity exhibited by the three terbenzimidazoles does not appear to be correlated with the abilities of these compounds to poison TOP1. (iii) Upon complexation with both poly(dA).poly(dT) and salmon testes DNA, the three terbenzimidazole analogues exhibit flow linear dichroism properties characteristic of a minor groove-directed mode of binding to these host DNA duplexes. (iv) The apparent minor groove binding affinities of the three terbenzimidazole analogues for the d(GA4T4C)2 duplex follow a qualitatively similar hierarchy to that noted above for ligand-induced poisoning of human TOP1-namely, 5PTB > TB > 5NIBB. In the aggregate, our results suggest that DNA minor groove binding, but not DNA unwinding, is important in the poisoning of TOP1 by terbenzimidazoles.

Animals↗

PubMed1998

Blocking GABA(A) receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat.

The effect of blocking the A subtype of gamma-aminobutyric acid (GABA(A)) receptors in the anterior ventral tegmental area (VTA) on ethanol (EtOH; 10% v/v) and saccharin (SACC; 0.0125%) consumption was investigated in alcohol-preferring P rats. Picrotoxin (0.005, 0.01, 0.05 and 0.10 microg/0.5 microl) was injected into the VTA, and consumption of EtOH and SACC was assessed in two 2-h limited-access drinking paradigms (concurrent EtOH/SACC access, and alternate-day-access to EtOH and SACC). Under concurrent-access conditions, the picrotoxin microinjections resulted in a 55 and 84% decrease in EtOH consumption at the 0.05 and 0.10 microg doses, respectively, compared with consumption following microinjections of vehicle solution (P<0.05). Saccharin intake was not significantly altered by picrotoxin. Under alternate-day-access drinking conditions, the picrotoxin microinjections resulted in dose-dependent decreases in EtOH consumption of 37-68%, with significant decreases following the 0.005, 0.05 and 0.10 microg doses (P<0.04). Saccharin intake was significantly reduced only at the 0.05 microg dose. The decrease in EtOH consumption after 0.10 microg picrotoxin was attenuated by co-administration of 0.01 microg muscimol. This dose of muscimol had no effect on EtOH consumption when injected alone. Intra-VTA injections of bicuculline (0.04 microg), another GABA(A) antagonist, reduced EtOH intake, comparable to the reduction following 0.10 microg picrotoxin. Microinjections of 0.10 microg picrotoxin in regions outside the VTA failed to decrease EtOH intake. These results suggest that anterior VTA mechanisms regulating alcohol drinking behavior are under tonic GABA inhibition, mediated by GABA(A) receptors. The results also suggest that different neural mechanisms are regulating voluntary EtOH and SACC drinking behaviors.

Alcohol Drinking↗

PubMed1998

Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines.

Selective breeding for voluntary alcohol consumption was utilized to establish the alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines. Inbreeding was initiated after 30 generations of selection and, after 19 generations of inbreeding, 384 F2 intercross progeny were created to identify quantitative trait loci (QTLs) influencing alcohol consumption. We had reported previously a QTL on Chromosome (Chr) 4; additional markers genotyped on Chr 4 have increased the maximum lod score from 8.6 to 9.2. This QTL acts in an additive fashion and continues to account for approximately 11% of the phenotypic variability. The 95% confidence interval is 12.5 cM and includes the candidate gene, neuropeptide Y. Subsequent to the identification of the QTL on Chr 4, a genome scan was completed to identify additional QTLs influencing alcohol consumption. A lod score of 2.5 was obtained on Chr 3, syntenic to a region previously reported for alcohol preference in mice. Analysis of Chr 8 produced a lod score of 2.2 near the dopamine D2 and serotonin 1b receptors, which have been previously reported as candidate genes for alcohol preference. Evidence for linkage to alcohol consumption was not found on any other chromosome. It therefore appears likely that, in addition to the QTL on Chr 4, multiple loci of small to moderate effect, such as those on Chrs 3 and 8, underlie the difference in alcohol consumption in the P/NP lines.

Alcohol Drinking↗

PubMed1998

Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass.

BACKGROUND & AIMS: Alcoholic liver disease purportedly develops more readily in women than in men. Some studies have demonstrated faster rates of alcohol elimination in women. This study examined whether gender differences in alcohol metabolism are related to differences in liver volume and/or differences in lean body mass. METHODS: Ten men and 10 women had alcohol elimination rates determined by clamping of the breath alcohol concentration at 50 mg/dL by means of a constant rate of intravenous infusion of 6% ethanol. Liver volume was determined by computed tomography. RESULTS: Mean alcohol elimination rate and mean computed liver volume were not significantly different in men and women. Lean body mass was 42% greater in men than in women. Consequently, the calculated alcohol elimination rate and liver volume per kilogram of lean body mass were 33% and 38% higher in women than in men, respectively. When the alcohol elimination rate was calculated per unit liver volume, no gender-related difference was found. CONCLUSIONS: Women have greater clearance of ethanol per unit lean body mass, confirming previous oral alcohol administration studies. Women have approximately the same liver volume as men, explaining the equivalent alcohol elimination rates seen when men and women are compared on the basis of liver size.

Adult↗

PubMed1998

GABA(A) receptor function in the cerebral cortex of alcohol-naive P and NP rats.

Previous studies have demonstrated an innate difference in the sensitivity of ethanol-naive P and NP rats to the acute intoxicating effects of high doses of ethanol. A number of studies have suggested that the acute intoxicating effects of ethanol may be mediated in part through potentiation of GABA(A)/benzodiazepine receptor function. In the present study, the function of GABA(A)/benzodiazepine receptors was studied in ethanol-naive alcohol-preferring (P) and -nonpreferring (NP) lines of rats by measuring 36Cl- influx into cortical microsacs. GABA, in a concentration-dependent manner, increased 36Cl- influx to an equivalent extent into cortical microsacs from P and NP rats (EC50 = 9.0 +/- 1.0 and 10 +/- 1.1 microM; Emax = 30.8 +/- 1.3 and 28.1 +/- 0.9 nmol Cl-/mg protein/3 s, respectively). Pentobarbital (30 microM) enhanced GABA-stimulated 36Cl- uptake (75 and 71% increase for P and NP rats, respectively) equally well in cortical microsacs from P and NP rats. Likewise, phenobarbital potentiation of GABA-stimulated 36Cl- influx was similar in cortical microsacs from P and NP rats. Phenobarbital, at the highest concentration tested (3 mM), directly stimulated 36Cl- influx to a similar extent in P and NP rats. However, ethanol failed to alter GABA-stimulated 36Cl- uptake into cortical microsacs prepared from ethanol-naive P and NP rats. The present results suggest that the differences between P and NP rats in innate sensitivity to the high dose effects of ethanol do not appear to be due to differences in cortical GABA(A) receptor function.

Animals↗

PubMed1998

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.

Alcoholism↗

PubMed1998

Serotonin3 receptor antagonism of alcohol intake: effects of drinking conditions.

The effects of 5-HT3 receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01-3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1-3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT3 antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT3 antagonists on ethanol intake.

Alcohol Drinking↗

PubMed1998

Quantitative autoradiography of mu-opioid receptors in the CNS of alcohol-naive alcohol-preferring P and -nonpreferring NP rats.

The densities of mu-opioid binding sites in the CNS of alcohol-naive adult male P and NP rats (N = 9 each line) were examined using quantitative autoradiography. Coronal sections (20 microm) were prepared from frozen brains and incubated in 5 nM [3H]DAMGO to label mu-opioid receptor sites. Nonspecific binding was determined in the presence of 1 microM DAMGO. The amount of [3H]DAMGO binding was (a) 20-25% higher in the olfactory tubercle, nucleus accumbens shell and core, and basolateral and lateral amygdaloid nuclei; (b) 15% higher in the lateral septal intermediate nucleus and caudate-putamen patches; and (c) 10-30% lower in the pyramidal and radiatum layers in the CA1 region of the anterior dorsal hippocampus, ventral dentate gyrus and CA1 pyramidal layer of the posterior hippocampus, and posterior medial cortical amygdaloid nucleus of the P compared to the NP rat. No line differences were found in any of the other regions examined (e.g., the cerebral cortical subregions and layers, thalamic nuclei, ventral tegmental area, ventral pallidum, lateral hypothalamus, other regions of the hippocampus, and several subcortical structures). The innate differences in the amount of binding to mu-opioid recognition sites in certain limbic structures, such as the nucleus accumbens, amygdala, and olfactory tubercle, of the P and NP lines may be factors contributing to their disparate alcohol drinking characteristics.

Alcohol Drinking↗

PubMed1998

Effects of isoflavones on alcohol pharmacokinetics and alcohol-drinking behavior in rats.

Puerarin, daidzin, and daidzein are 3 major isoflavonoid compounds isolated from Pueraria lobata, an edible vine used widely in China for various medicinal purposes. We studied the antiinebriation and the antidipsotropic effects of these antioxidants in rats. Daidzin and daidzein shortened alcohol-induced sleep time (loss of righting reflex) in rats that were given ethanol intragastrically but not in those given ethanol intraperitoneally. When daidzin was given to animals intragastrically with the ethanol solution, the blood alcohol concentration (BAC) was found to peak later and be lower than in control rats that were given only the ethanol solution. BACs also receded more slowly if daidzin was fed to the animals. None of the 3 isoflavonoid compounds administered orally affected liver alcohol dehydrogenase or aldehyde dehydrogenase activities, as was reported for intraperitoneal administration. Further experiments indicated that the suppression of the BAC by daidzin was due mainly to delay of stomach emptying. All 3 compounds suppressed voluntary alcohol consumption in alcohol-preferring rats. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total volume of liquid consumed daily remained unchanged. Daily food consumption and body weight gain were not affected. Alcohol preference returned to baseline levels after the isoflavonoids were discontinued. We postulate that the suppression of alcohol reinforcement produced by these compounds is mediated centrally in the brain reward pathway.

Alcohol Deterrents↗