ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00948.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Most responses to alcohol in both humans and animals are heritable, and this genetic sensitivity to ethanol is determined by multiple genes. However, the number of genes, their identities, and just how they determine susceptibility to the actions of alcohol are unknown. Herein, we describe a multistage strategy for mapping quantitative trait loci (QTLs) using recombinant inbred strains and F2 mice. Precise mapping of the chromosome positions of these QTLs should increase our understanding of the genetic causes for individual differences in behavioral sensitivity to alcohol by (1) identifying genomic markers associated with sensitivity to alcohol, (2) allowing the genes specifying behavior to be cloned by position, and (3) elucidating “candidate” genes demonstrating linkage to markers associated with behavioral responses to alcohol. Syntenic conservation between the mouse and human genomes should facilitate the eventual mapping and cloning of human homologs of these QTLs. Ultimately, cloning of these genes may allow the development of gene therapies or other therapeutic interventions for management or prevention of alcoholism and alcohol ab

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00949.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Theoretical descriptions are given for two breeding methods in animal genetics that might be of use In alcohol research. These methods are marker‐based selection and marker‐based development of congenic strains, both using DNA markers such as polymerase chain reaction‐detectable polymorphisms as the criteria for breeding. Such designs would utilize these markers as Indicators of adjacent Quantitative Trait Loci (QTL) that are influential on alcohol‐related phenotypes. Issues in the logic and implementation of these methods, such as proximity of the markers and the QTL allele, are explored. A third method, development of congenic strains with phenotypic screening, is also described. This method is currently being used to create two sets of congenic lines on a C57BL/6 inbred mouse background. The criterion phenotype is locomotor activation to 1.5 g/kg (ip) ethanol. Data are reported on the success of transferring the activation phenotype from two strains, DBA/2Abg and MOLD/Rk‐Abg, onto the nonactivated C57BL/6Abg background. The value of these methods in alcohol research is outlined with regard to both identification of relevant genes and for their use as tools in basic research on mechanism of alcoh

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00950.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Behavioral and biochemical responses mediating ethanol's actions have been difficult to study in humans and animals because of their complex polygenic nature. Recent progress in the creation of new animal models using recombinant DNA technology has provided a set of genetic tools by which the role of specific candidate genes in ethanol's actions can be examined. These techniques include the creation of transgenic and null mutant mice, as well as manipulation of protein synthesis with antisense treatments. These techniques are reviewed, and their potential applications to alcohol research are discussed.

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00951.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

We describe a method for the rapid identification and mapping of human genes, including those possibly contributing to disease and alcohol‐related phenotypes. New human genes are identified from cDNA libraries through single‐pass sequencing into the 3′ untranslated (3′UT) regions of human brain cDNAs. Primers derived from the 3′UT region sequences [representing gene‐based, sequence‐tagged sites (STSs)] are used for polymerase chain reaction (PCR) analyses of the CEPH megabase insert yeast artificial chromosome (YAC) DNA pools. With this approach, ∼18,000 megabase YACs can be screened and a single YAC identified using only 52 PCR reactions. The YAC localization in conjunction with other mapping techniques, such as PCR mapping to human chromosomes using somatic cell hybrids, allows identification of chromosomal band locations. In this manner, each gene can be associated with its own STS, which in turn specifies both a corresponding genomic clone and specific location in the genome. These locations can be compared with the purported locations of disease genes. The locations of the STSs can also be compared with those of Quantitative Trait Loci implicated for quantitative traits (e.g., alcohol‐related phenotypes) on the basis of synteny between the mouse and human genes. Using this strategy, we found candidates for 78 human disease/syndrome genes among the first

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00952.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Identification of vulnerability alleles is one starting point for elucidating the web of interactions leading to alcoholism so that treatment and prevention can be improved. Heritability studies indicate that vulnerability alleles exist. Two molecular approaches for identifying them, direct analysis of candidate genes and genetic linkage, are highlighted in this review. Methodological problems that have been partially addressed and limitations for the applicability of the genetic findings are discussed.

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00953.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00954.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Gram‐negative sepsis causes a depression of the myocardium such that ventricular function curves generated on isolated perfused hearts removed from septic rats are displaced downward and to the right of control. Alcohol consumption can also cause a depression of the myocardium, especially if the period of alcohol feeding is prolonged. However, even before overt changes in the myocardium can be measured as a result of alcohol consumption, chronic alcoholism can result in a potentiation of sepsis‐induced cardiac depression (Am. J. Physiol.250:H1857‐H1863, 1991). The purpose of the present study was to determine if 1 week of withdrawal of alcohol from the diet after 8 weeks of alcohol consumption would reverse the potentiation by alcohol of sepsis‐induced cardiac depression. Animals were fed an ethanol‐containing diet in which ethanol contributed 36% of the total calories. Rats were fed this diet or a control liquid diet for 8 weeks, and then some animals were taken off the alcohol diet and placed on the control diet for 1 week. Sepsis was induced in control‐fed, alcohol‐fed or withdrawal animals by the administration ofEscherichia coliinto the dorsal subcutaneous space. Nonseptic animals received sterile saline in this space. The following day animals were anesthetized, and the hearts were removed and studied as isolated working hearts. Hearts removed from septic and alcohol septic animals showed severe depression of cardiac contractile performance. Hearts from the withdrawal group, however, were less compromised by sepsis and showed only a few signs of cardiac dysfunction. Withdrawal from alcohol for 1 week thus resulted in protection of the heart from sepsis‐induced car

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00955.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

This series of experiments measured ethanol‐induced changes In levels of tree Intracelular calcium. Cerebellar macroneurons, harvested from rat embryos on embryonic day 17, were cultured In the presence of 75 mM ethanol for 24,48, or 96 hr. Intracellular calcium concentrations in control and ethanol‐exposed neurons did not differ after 24 hr, but they were significantly elevated In the neurons exposed to ethanol for 48 or 96 hr. Similarly, Increases In intracellular calcium elicited by stimulation wk 50 μM NMDA were not significantly different In control and ethanol‐exposed neurons after 24 hr. After 48 and 96 hr, however, NMDA‐stimulated Increases in Intracellular calcium levels in control neurons were significantly greater than in the ethanol‐exposed neurons. These results showed that, when calcium levels were elevated by prolonged exposure to ethanol, the neurons were significantly less responsive to NMDA stimulation. Increases in intracelular calcium elicited by stimulation with 30 mM KCI were not significantly different in the control and treated neurons after 24 and 48 hr of ethanol exposure. After 96 hr of exposure to ethanol, however, them was a significant Increase In intracellular calcium levels In control neurons following KCI stimulation, but not in the ethanol‐exposed neurons. The fact that neuronal responses to KCI stimulation were depressed only following 96 hr of exposure to ethanol makes it unlikely that voltage‐regulated channels were the primary mediators of the ethanol‐induced elevations in intracellular calcium in chronically

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00956.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Neuronal cell loss is one of the most debilitating effects of alcohol exposure during development of the nervous system. In this study, primary cultures of neuronal cells (cerebellar granule cells) were wed to examine mechanisms of alcohol‐induced neuronal cell death. Previously, we established that (Pantazis et al., Alcohol Clin Exp Re8 17:1014–1021,1993): (1) alcohol exposure caused neuronal cell death in cultures of cerebellar granule cells and this cell loss was both time‐dependent and dose‐dependent; and (2) the vulnerability of cerebellar granule cells to alcohol‐induced loss changed with the length of time the cells were in culture before Initiating alcohol exposure—that is, younger cultures (1 day in vitro) were much more susceptible to alcohol‐induced neuronal cell death than older cultures (4 or 7 days in vitro). The primary goal of the present study was to examine the potential role of the NMDA receptor in alcohol‐induced death of cerebellar granule cells in culture. Experiments were performed to test the hypothesis that the alcohol‐induced death of cerebellar granule cells can be prevented or reduced by NMDA treatment Our results Indicate that stimulation of the NMDA receptor has a neuroprotective effect and can significantly reduce the alcohol‐induced neuronal cell death of newly established cerebellar granule cell cultures. This neuroprotective effect of NMDA is blocked by 2‐amlno‐5‐phosphonovalerate, a come inhibitor of the NMDA receptor, Confirming that this neuroprotective effect is mediated via the NMDA receptor. This is the first report that alcohol's neurotoxic effect can be ameliorated by activa

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1995.tb00957.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY