Biomedical subjects

T K Li

Publications and source records attributed to T K Li.

At least 19 recordsLinked to original sources

PubMed1999

Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress.

Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), is known to induce oxidative stress and apoptosis. U937 cells treated with H2O2 were shown to produce high molecular weight (HMW) DNA fragments approximately 50 to 100 kb in size in <1 min. The formation of these HMW DNA fragments is reversible and shown to be mediated by DNA topoisomerase II (TOP2). Following this initial event, formation of irreversible HMW DNA fragments and nucleosomal ladders occurs. Our results thus demonstrate a potential role of TOP2 in oxidative damage of DNA and apoptotic cell death.

DNA Damage↗

PubMed1999

The pH-dependent binding of NADH and subsequent enzyme isomerization of human liver beta 3 beta 3 alcohol dehydrogenase.

Human class I beta 3 beta 3 is one of the alcohol dehydrogenase dimers that catalyzes the reversible oxidation of ethanol. The beta 3 subunit has a Cys substitution for Arg-369 (beta 369C) in the coenzyme-binding site of the beta1 subunit. Kinetic studies have demonstrated that this natural mutation in the coenzyme-binding site decreases affinity for NAD+ and NADH. Structural studies suggest that the enzyme isomerizes from an open to closed form with coenzyme binding. However, the extent to which this isomerization limits catalysis is not known. In this study, stopped-flow kinetics were used from pH 6 to 9 with recombinant beta 369C to evaluate rate-limiting steps in coenzyme association and catalysis. Association rates of NADH approached an apparent zero-order rate with increasing NADH concentrations at pH 7.5 (42 +/- 1 s-1). This observation is consistent with an NADH-induced isomerization of the enzyme from an open to closed conformation. The pH dependence of apparent zero-order rate constants fit best a model in which a single ionization limits diminishing rates (pKa = 7.2 +/- 0.1), and coincided with Vmax values for acetaldehyde reduction. This indicates that NADH-induced isomerization to a closed conformation may be rate-limiting for acetaldehyde reduction. The pH dependence of equilibrium NADH-binding constants fits best a model in which a single ionization leads to a loss in NADH affinity (pKa = 8.1 +/- 0. 2). Rate constants for isomerization from a closed to open conformation were also calculated, and these values coincided with Vmax for ethanol oxidation above pH 7.5. This suggests that NADH-induced isomerization of beta 369C from a closed to open conformation is rate-limiting for ethanol oxidation above pH 7.5.

Acetaldehyde↗

PubMed1999

Electrophysiological response to neuropeptide Y (NPY): in alcohol-naive preferring and non-preferring rats.

Electroencephalograms (EEGs) and event-related potentials (ERPs) to auditory stimuli were recorded following intracerebroventricular administration of neuropeptide Y (saline, NPY: 1.0, 3.0 nmol) in two lines of rats that have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Previous studies have demonstrated that NPY has a distinct electrophysiological profile that is similar to that of ethanol. In outbred Wistar rats, both NPY and ethanol produced highly significant decreases in the amplitude and increases in the latency of the N1 component of the ERP to all three auditory stimuli. Because the N1 has been associated with attention, these data suggest that both NPY and alcohol may diminish attentional processes. In the present study, NPY-induced decreases in N1 amplitude were also found, but only to the frequently presented tone. This suggests that both P and NP rats may have attenuated responses to NPY's effects on attention/arousal. Like outbred Wistars, P and NP rats were also found to have significant NPY-induced increases in N1 latency in the cortex and hippocampus. However, in the amygdala, while P rats evidenced increases in N1 latency and decreases in N1 amplitudes, NP rats displayed the opposite effects. Spectral analysis revealed that NPY also produced differential EEG responses in P and NP rats. In previous studies in outbred Wistar rats NPY has been found to produce slowing of delta (1-2 Hz) frequencies at the 1-nmol dose and reductions in power, particularly in the higher frequencies in the amygdala, at the 3-nmol dose. This electrophysiological profile is not unlike what is seen following alcohol and benzodiazepines and is associated with anxiolysis. P rats were found to have this general pattern of EEG responses to NPY but attenuated suggesting that they may have reduced responses to electrophysiological measures of the anxiolytic effects of NPY. In contrast, NP rats had NPY-induced EEG effects in amygdala and frontal cortex that were opposite to those seen in P rats. These opposing responses to NPY tended to produce a "normalization" of the power differences that existed between the two rat lines at baseline. Taken together with previous findings that P rats have decreased NPY concentrations in limbic and frontal cortical sites, these data suggest that differences in the regulation of NPY neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.

Alcohol Drinking↗

PubMed1999

Neurontensin studies in alcohol naive, preferring and non-preferring rats.

Neurotensin is a tridecapeptide, present in the central nervous system and the gastrointestinal tract in man and animals. Previous studies in mice selectively bred for differences in hypnotic sensitivity to ethanol have provided data to suggest that neurotensinergic systems may mediate differences in ethanol's actions in these animals. The present study sought to determine if brain neurotensin levels differed between two lines of rats which have been selectively bred for alcohol preferring or non-preferring behaviors. In addition, electroencephalographic and event-related potential responses to intracerebroventricular saline and neurotensin (10 or 30 microg) were evaluated between the rat lines. Similar to human subjects at high genetic risk for alcoholism, preferring rats were found to have more electroencephalographic fast frequency activity and lowered amplitude of the P3 component of the event-related potential in cortical sites under the saline condition. Overall, electrophysiological response to neurotensin, in the two rats lines, was substantially similar to what has been reported previously in outbred Wistar rats, and consisted of dose-related decreases in overall electroencephalographic spectral power concomitant with increases in amplitude and decreases in the latency of the N1 component of the event-related potential. However, differences in neurotensin responses between the preferring and non-preferring rat lines were also found. The differences in electroencephalographic high-frequency activity and in P3 amplitude seen between the rat lines under control conditions were eliminated by administration of neurotensin. In addition, preferring rats appeared to be more sensitive to neurotensin-induced increases in N1 amplitude. Brain neurotensin concentrations were also found to differ between the lines. Significantly lower concentrations of neurotensin were found in the frontal cortex of preferring rats when compared to non-preferring rats or outbred Wistars. Taken together, these studies suggest that differences in the regulation of neurotensin neurons may contribute to the expression of behavioral preference for ethanol consumption in selective rat lines. Additionally, drugs targeting the neurotensinergic system may plausibly be of utility in the treatment of alcoholism.

Acoustic Stimulation↗

PubMed1999

Selective breeding for high and low alcohol preference in mice.

High and low alcohol preference (HAP and LAP, respectively) mice were created by 10 generations of bidirectional selection for differences in two-bottle choice alcohol consumption. The progenitors used for selection were HS/lbg mice, which are a genetically defined, outbred stock. During selection, mice had 24-h, daily access to 10% alcohol (v/v) and water ad libitum for 30 days and were selected based on the alcohol (g/kg) consumed per day over the entire period. Food was available ad libitum. At S10, line means for alcohol consumption differed greatly, with consumption of over 12 g/kg per day in the HAP mice and less than 2 g/kg per day in the LAP mice. Realized heritability for bidirectional selection was approximately 0.2. Female mice consumed more alcohol than male mice. There were no differences between lines in alcohol elimination rate, nor were there line differences in intake of salt or quinine solutions. However, consumption of saccharin solutions was greater in HAP mice than LAP mice, consistent with previous findings of a genetic correlation between sweet preference and alcohol drinking. Because the mouse genome is relatively well characterized, these selected lines should prove a useful tool for assessment of the genetic basis of, and phenotypes that correlate with, alcohol drinking.

Alcohol Drinking↗

PubMed1999

Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.

Adult↗

PubMed1999

Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component.

OBJECTIVE: The DSM-IV work group asked researchers and clinicians to subtype substance dependent individuals according to the presence or absence of physiological symptoms. A recent report from the Collaborative Study on the Genetics of Alcoholism demonstrated that among alcohol-dependent men and women, a history of tolerance or withdrawal was associated with a more severe clinical course, especially for individuals with histories of alcohol withdrawal. This article evaluates similar distinctions among subjects in the collaborative study who were dependent on marijuana, cocaine, amphetamines, or opiates. METHOD: Structured interviews gathered information from 1,457 individuals with a lifetime diagnosis of marijuana dependence, 1,262 with histories of cocaine dependence, 647 with amphetamine dependence, and 368 subjects with opiate dependence. For each drug, the clinical course was compared for subjects whose dependence included a history of withdrawal (group 1), those dependent on each drug who denied withdrawal but reported tolerance (group 2), and those who denied both tolerance and withdrawal (group 3). RESULTS: The proportion of dependent individuals who denied tolerance or withdrawal (group 3) ranged from 30% for marijuana to 4% for opiates. For each substance, individuals in groups 1 and 2 evidenced more severe substance-related problems and at least a trend for greater intensities of exposure to the drug; those reporting withdrawal (group 1) showed the greatest intensity of problems. CONCLUSIONS: The designation of dependence in the context of tolerance or withdrawal identifies individuals with more severe clinical histories. These results support the importance of the designation of a physiological component to dependence, especially for people who have experienced a withdrawal syndrome.

Adult↗

PubMed1999

A twin study of genetic influences on the acute adaptation of the EEG to alcohol.

A two-dose alcohol challenge protocol was used to study genetic influences on the acute adaptation of the EEG to alcohol in 53 monozygotic and 38 same-sex dizygotic Caucasian twin pairs averaging 30 years of age. Equal doses of alcohol were administered at 10:00 and 11:00 AM, yielding mean peak breath alcohol concentrations of 0.057% and 0.099%, respectively. Eyes-closed, resting EEG was recorded four times: at baseline; on the ascending limb of the overall experiment at a breath alcohol concentration (BrAC) near 0.06%; on the descending limb at a BrAC near the value when the subject's EEG was obtained on the ascending limb; and, finally, when the BrAC fell to 0.02%. Genetic analyses of log-transformed values of total spectral power (L10TSP) and spectral band power (L10SBP) were performed on EEG spectra averaged across all 17 scalp lead locations. After adjusting for body weight, a significant fraction of population variance in L10TSP was attributable to genetic influence: H2 values for TSP were 0.73, 0.72, and 0.73 at the three postalcohol EEG recordings, respectively. Similar findings pertained to each L10SBP at each postalcohol recording, except forthe delta band. The change in postethanol EEG power was examined for evidence that genes influence acute adaptations in brain function. Descending-minus-ascending limb L10TSP was normalized by the individual's ascending limb L10TSP to minimize nonalcohol-related effects that can influence both measurements. Earlier analyses of the same sample's initial EEG response to alcohol noted a substantial increase in the ascending limb EEG power, compared with baseline. Thus, positive values of the postethanol change denote a progression away from baseline attributable to acute sensitization to alcohol; negative values signify a return toward baseline values suggesting acute tolerance to alcohol. Genetic analysis of the normalized difference in L10TSP had a highly significant H2 value of 0.70, indicating that both acute tolerance and acute sensitization to alcohol may represent adaptations reflecting substantial heritable influence. Slightly smaller, but significant values of H2 for the normalized difference in L10SPB were observed for delta, alpha-slow and beta-slow frequency bands. In contrast, H2 for the differences between the final and ascending limb EEG power were not significant, except for the theta band. Thus, heritable drowsiness may have contributed to detection of genetic influences on acute adaptation, but represent a potential confound only in the theta band.

Adaptation, Physiological↗

PubMed1999

A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping.

Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (i.v.) infusion of an ethanol solution at a rate that is intermittently adjusted based on real-time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The "quick-clamping" method replaced the oral loading dose with a preprogrammed infusion rate profile. A three-compartment physiologically-based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion-rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two-session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/i.v. method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean +/- SE for quick-clamp: 17 +/- 4 min; for oral/i.v. clamp: 45 +/- 7 min). The quick-clamping method enables, for the first time, the examination of the early-phase neuroadaptive responses to alcohol in human subjects.

Alcohol Drinking↗

PubMed1999

Differences in neurophysiological indices of associative learning in alcohol-preferring and nonpreferring rats.

Alcohol-preferring (P) and -nonpreferring (NP) rats differ in baseline neurophysiological measures as well as in their neurophysiological responses to ethanol. In the present study, these lines of rats were assessed to determine whether they also differ in their neurophysiological responses during an associative learning paradigm. Male P and NP rats were implanted with electrodes in the frontal cortex, parietal cortex, and amygdala. Both groups were then exposed to an associative learning paradigm. During the first five sessions (conditioning phase), an infrequently presented tone was paired with the delivery of a food pellet. A second tone was also presented during these sessions, but this tone was never paired with food pellet presentation. During the second five sessions (extinction phase), neither of the tones were paired with food pellet presentation. Event-related potentials (ERPs) in response to the tones were recorded during both phases of the experiment. During the first session, the latency of the N1 and P3 waves from the cortical lead in response to the food-paired tone was significantly longer in the NP rats than in P rats. In addition, P rats displayed significant increases in the latency of the P2 wave component in the cortex and the P3A wave component in the amygdala in response to changes in the association between food pellet and tone presentation. These data indicate that the P rats were more responsive to changes in the association between food pellet delivery and tone presentation. They also suggest more enhanced associative learning in P rats than in NP rats. This enhanced learning could be an innate trait of P rats or the result of altered learning due to differences in anxiety between P and NP rats.

Acoustic Stimulation↗

PubMed1999

Limited access alcohol drinking in high- and low-alcohol preferring selected lines of mice.

BACKGROUND: Selection studies and genetic analyses of drinking behavior in rodents often involved unlimited access to alcohol over a period of weeks, with water and food freely available. Most studies investigating the pharmacology of alcohol drinking, on the other hand, use procedures in which access to alcohol is limited to a particular time each day. Reconciliation of findings between these two conditions likely depends on their sharing common genetic mechanisms as indicated, for example, by covariation in response to selection. To this end, high- and low-alcohol preferring (HAP and LAP, respectively) mice, selected for differences in 24-hr access alcohol drinking over a 4-week period, were subjected to a limited access alcohol drinking protocol. METHODS: During 2-hr sessions, mice had access to various concentrations of alcohol (7-15%, v/v) in the home cage for 2 hr a day, with ad libitum access to food and water. Additional sessions were conducted with no food present. RESULTS: Although both strains consumed alcohol and water during these sessions, HAP mice drank far more alcohol than did LAP mice. HAP but not LAP mice drank alcohol at a high rate early in the session compared with later in the session. Additionally, HAP mice responded to changes in alcohol concentration, whereas LAP mice did not. Removal of food did not influence alcohol drinking, although water drinking decreased following food removal. HAP mice reached appreciable blood alcohol concentrations after limited access. CONCLUSIONS: These findings indicate that in these selectively bred mice, alcohol drinking during limited and unlimited access may be genetically related, and that drinking during limited access sessions in HAP mice is likely for the pharmacological properties of alcohol.

Alcohol Drinking↗

PubMed1999

Innate differences of neuropeptide Y (NPY) in hypothalamic nuclei and central nucleus of the amygdala between selectively bred rats with high and low alcohol preference.

BACKGROUND: Neuropeptide Y (NPY) is a neuropeptide that has been demonstrated to produce anxiolytic effects when administered centrally. To examine the hypothesis that NPY might play a role in alcohol-seeking behavior, this study took advantage of the genetic differences of the alcohol-preferring (P) rats and alcohol-nonpreferring (NP) rats, as well as the high alcohol-drinking (HAD) rats and low alcohol-drinking (LAD) rats, in voluntary alcohol consumption to examine if NPY neurons in the brains differ between these selected lines. METHODS: The NPY immunoreactivity (NPY-I) was measured using an established radioimmunohistochemical assay in discrete brain structures including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARC), and central nucleus of the amygdala (CeA). RESULTS: The quantitative data indicated that there was more NPY-I in the PVN and ARC of P rats than NP rats, whereas there was less NPY-I in the PVN and ARC of HAD rats than LAD rats. However, the NPY-I in the CeA was less in both the P and HAD rats than in the NP and LAD rats, respectively. Therefore, the data indicate that there are innate differences in the NPY-I in the brain between selectively bred rats with high and low alcohol preference. CONCLUSION: Because both P rats and HAD rats have high alcohol preference, the disparate finding between these two lines of rats suggests that the hypothalamic NPY neurons are probably not associated with alcohol preference. In contrast, consistent findings in the CeA of both P rats and HAD rats suggest that NPY in the CeA of P and HAD rats may contribute to the regulation of alcohol consumption. This is substantiated by a recent report showing that NPY-knockout mice drink significantly more ethanol, and transgenic mice that overexpress the NPY gene drink less alcohol, than wild-type mice. Together, the findings support the notion that NPY agonists that would enhance NPY function in the amygdala might be useful for the treatment of anxiety and alcoholism.

Alcohol Drinking↗

PubMed1999

A preliminary study of acute responses to clamped alcohol concentration and family history of alcoholism.

BACKGROUND: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). METHODS: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60+/-5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability (r>0.6). RESULTS: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. CONCLUSIONS: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.

Adult↗

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↗