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Ethanol Sensitivity (ethanol + sensitivity)

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Life Sciences	16%

Selected Abstracts

Ethanol-Regulated Genes That Contribute to Ethanol Sensitivity and Rapid Tolerance in Drosophila

ALCOHOLISM, Issue 2 2010
Eric C. Kong
Background:, Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. Methods:, To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila, and completed a behavioral survey of strains harboring mutations in ethanol-regulated genes. Results:, Enrichment for genes in metabolism, nucleic acid binding, olfaction, regulation of signal transduction, and stress suggests that these biological processes are coordinately affected by ethanol exposure. We also detected a coordinate up-regulation of genes in the Toll and Imd innate immunity signal transduction pathways. A multi-study comparison revealed a small set of genes showing similar regulation, including increased expression of 3 genes for serine biosynthesis. A survey of Drosophila strains harboring mutations in ethanol-regulated genes for ethanol sensitivity and tolerance phenotypes revealed roles for serine biosynthesis, olfaction, transcriptional regulation, immunity, and metabolism. Flies harboring deletions of the genes encoding the olfactory co-receptor Or83b or the sirtuin Sir2 showed marked changes in the development of ethanol tolerance. Conclusions:, Our findings implicate novel roles for these genes in regulating ethanol behavioral responses. [source]

An Assay for Evoked Locomotor Behavior in Drosophila Reveals a Role for Integrins in Ethanol Sensitivity and Rapid Ethanol Tolerance

ALCOHOLISM, Issue 10 2009
Poonam Bhandari
Background:, Ethanol induces similar behavioral responses in mammals and the fruit fly, Drosophila melanogaster. By coupling assays for ethanol-related behavior to the genetic tools available in flies, a number of genes have been identified that influence physiological responses to ethanol. To enhance the utility of the Drosophila model for investigating genes involved in ethanol-related behavior, we explored the value of an assay that measures the sedative effects of ethanol on negative geotaxis, an evoked locomotor response. Methods:, We established eRING (ethanol Rapid Iterative Negative Geotaxis) as an assay for quantitating the sedative effects of ethanol on negative geotaxis (i.e., startle-induced climbing). We validated the assay by assessing acute sensitivity to ethanol and rapid ethanol tolerance in several different control strains and in flies with mutations known to disrupt these behaviors. We also used eRING in a candidate screen to identify mutants with altered ethanol-related behaviors. Results:, Negative geotaxis measured in eRING assays was dose-dependently impaired by ethanol exposure. Flies developed tolerance to the intoxicating effects of ethanol when tested during a second exposure. Ethanol sensitivity and rapid ethanol tolerance varied across 4 control strains, but internal ethanol concentrations were indistinguishable in the 4 strains during a first and second challenge with ethanol. Ethanol sensitivity and rapid ethanol tolerance, respectively, were altered in flies with mutations in amnesiac and hangover, genes known to influence these traits. Additionally, mutations in the , integrin gene myospheroid and the , integrin gene scab increased the initial sensitivity to ethanol and enhanced the development of rapid ethanol tolerance without altering internal ethanol concentrations. Conclusions:, The eRING assay is suitable for investigating genetic mechanisms that influence ethanol sensitivity and rapid ethanol tolerance. Ethanol sensitivity and rapid ethanol tolerance depend on the function of , and , integrins in flies. [source]

Cerebellar Gene Expression Profiling and eQTL Analysis in Inbred Mouse Strains Selected for Ethanol Sensitivity

ALCOHOLISM, Issue 9 2005
Erik J. MacLaren
Background: Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice exhibit striking differences in a number of alcohol and drug related behaviors. This study examined the expression levels of more than 39,000 transcripts in these strains in the cerebellum, a major target of ethanol's actions in the CNS, to find differentially expressed (DE) candidate genes for these phenotypes. Methods: Genes that were differentially expressed between the strains were identified using oligonucleotide arrays as well as complimentary DNA arrays. Sequence alignment was used to locate DE genes in the mouse genome assembly. In silico expression QTL (eQTL) mapping was used to identify chromosomal regions likely to control the transcription level of DE genes, and the EASE program identified overrepresented functional themes. The genomic region immediately upstream of the cyclase associated protein homolog 1 (Cap1) gene was directly sequenced from PCR products. Results: Nearly 300 genes were identified as differentially expressed between the cerebella of ILS and ISS. These genes and their corresponding eQTLs map to genomic regions linked to several phenotypes that differ between the ILS and ISS strains, including ethanol preference and cocaine-induced locomotor activation on Chromosomes 4 and 7 respectively. Eight genes were cross-platform validated, four of which are more highly expressed in ILS cerebellum. Three SNPs, one of which disrupts a predicted Sp1 binding site, were found in the upstream region of Cap1, a strong candidate for influencing ethanol phenotypes. Conclusions: Many of these DE genes are candidates to influence ethanol and drug regulated phenotypes because they either map to ethanol related QTLs in the genome or are linked to them through eQTL mapping. Genes involved in calcium ion binding and transcriptional regulation are overrepresented and therefore these gene classes may influence ethanol behaviors in mice and humans. [source]

A Mutation in Mitochondrial Complex I Increases Ethanol Sensitivity in Caenorhabditis elegans

ALCOHOLISM, Issue 4 2003
Ernst-Bernhard Kayser
Background: The gene gas-1 encodes the 49-kDa subunit of complex I of the mitochondrial electron transport chain in Caenorhabditis elegans. A mutation in gas-1 profoundly increases sensitivity to ethanol and decreases complex I-dependent metabolism in mitochondria. Methods: Mitochondria were isolated from wild-type and gas-1 strains of C. elegans. The effects of ethanol on complex I-, II-, and III-dependent oxidative phosphorylation were measured for mitochondria from each strain. Reversibility of the effects of ethanol was determined by measuring oxidative phosphorylation after removal of mitochondria from 1.5 M ethanol. The effects of ethanol on mitochondrial structure were visualized with electron microscopy. Results: We found that ethanol inhibited complex I,, II,, and III,dependent oxidative phosphorylation in isolated wild-type mitochondria at concentrations that immobilize intact worms. It is important to note that the inhibitory effects of ethanol on mitochondria from either C. elegans or rat skeletal muscle were reversible even at molar concentrations. Complex I activity was lower in mitochondria from gas-1 animals than in mitochondria from wild-type animals at equal ethanol concentrations. Complex II activity was higher in gas-1 than in wild-type mitochondria at all concentrations of ethanol. No difference was seen between the strains in the sensitivity of complex III to ethanol. Conclusions: The difference in ethanol sensitivities between gas-1 and wild-type nematodes results solely from altered complex I function. At the respective concentrations of ethanol that immobilize whole animals, mitochondria from each strain of worms displayed identical rates of complex I-dependent state 3 respiration. We conclude that a threshold value of complex I activity controls the transition from mobility to immobility of C. elegans. [source]

Quantitative Trait Loci Affecting Ethanol Sensitivity in BXD Recombinant Inbred Mice

ALCOHOLISM, Issue 1 2000
Kaitlin E. Browman
Background: Genetic and environmental factors contribute to an individual's sensitivity to ethanol, although the exact genes underlying ethanol's effects are not known. Quantitative trait locus (QTL) mapping is one successful method for provisionally identifying genes participating in the mediation of a given behavior. QTL analyses seek to identify associations between a quantitative response and previously mapped marker genes across genetically diverse individuals. Many QTL analyses have been performed in BXD recombinant inbred (RI) strains of mice derived from a cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Methods: We conducted a QTL analysis of ethanol-induced loss of righting reflex and ataxia using a panel of 25 BXD RI strains and the progenitors B6 and D2. We measured the duration of loss of righting reflex after injection and blood ethanol concentrations upon regaining of righting reflex. Ataxia was measured as the latency to fall from a vertical screen. Results: Genome-wide QTL analyses correlating strain means with allelic status at >1500 markers identified several associations (p, 0.01). These provisional QTLs were on all chromosomes except 2,5,12,13, and X, and several map near potential candidate genes. Conclusions: These results suggest that ethanol sensitivity is determined by the actions of multiple genes and further suggest their general chromosomal map locations. These provisional linkages will now be confirmed or rejected using additional genetically segregating populations. [source]

An Assay for Evoked Locomotor Behavior in Drosophila Reveals a Role for Integrins in Ethanol Sensitivity and Rapid Ethanol Tolerance

A Mutation in Mitochondrial Complex I Increases Ethanol Sensitivity in Caenorhabditis elegans

PRECLINICAL STUDY: Circadian regulation of central ethanol sensitivity by the mPer2 gene

ADDICTION BIOLOGY, Issue 3 2009
Stéphanie Perreau-Lenz
ABSTRACT The effect of alcohol is known to vary with the time of the day. Although initially it was suggested that this phenomenon may be due to diurnal differences in ethanol metabolism, more recent studies were contradicting. In the present study, we therefore first set out in assessing the diurnal variations in ethanol sensitivity in mice analysing, concurrently, ethanol elimination rates. Ethanol-induced (3.5 g/kg; intraperitoneal) loss of righting reflex (LORR) duration was thus determined at several Zeitgeber time (ZT) points (ZT5, 11, 17 and 23) in C57BL/6N mice. In parallel, the corresponding ethanol elimination rates were also assessed. The results display the existence of a distinct diurnal rhythm in LORR duration peaking at ZT11, whereas no differences could be observed regarding the elimination rates of alcohol. Successively, we checked the involvement of the clock genes mPer1 and mPer2 in conveying this rhythm in sensitivity, testing LORR and hypothermia at the peak and trough previously observed (ZT5 and ZT11). Per1Brdm1 mice demonstrate a similar diurnal pattern as control mice, with enhanced LORR durations at ZT11. In contrast, Per2Brdm1 mice did not exhibit a temporal variation to the depressant effects of ethanol with respect to LORR, revealing a constant high sensitivity to ethanol. The present study reveals a central role of the mPer2 gene in inhibiting alcohol sensitivity at the beginning of the inactive phase. [source]

Sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone: a quantitative trait locus study of common genetic influence

GENES, BRAIN AND BEHAVIOR, Issue 7 2006
A. A. Palmer
Previous studies have suggested that common genetic mechanisms influence sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone. We conducted two quantitative trait locus (QTL) studies to identify chromosomal regions that harbor genes that influence locomotor response to ethanol (2 g/kg) and allopregnanolone (17 mg/kg) using F2 crosses between C57BL/6J and DBA/2J mice. Because our previous data from the BXD recombinant inbred strains had indicated that chromosome 2 contained QTL for sensitivity to the locomotor-stimulant effects of both ethanol and allopregnanolone, we also tested reciprocal chromosome 2 congenic strains for sensitivity to the locomotor-stimulant effects of both drugs. The F2 analysis for ethanol sensitivity identified significant QTL on chromosomes 1 and 2 and suggestive QTL on chromosomes 5 and 9. The analysis of the allopregnanolone F2 study identified suggestive QTL on chromosomes 3, 5 and 12. Suggestive evidence for a female-specific QTL on chromosome 2 was also found. The studies of congenic mouse strains indicated that both the congenic strains captured one or more QTL for sensitivity to the locomotor-stimulant effects of both ethanol (2 g/kg) and allopregnanolone (17 mg/kg). When Fisher's method was used to combine the P values for the RI, F2 and congenic studies of the chromosome 2 QTL, cumulative probability scores of 9.6 × 10,15 for ethanol and 7.7 × 10,7 for allopregnanolone were obtained. These results confirm the presence of QTL for ethanol and allopregnanolone sensitivity in a common region of chromosome 2 and suggest possible pleiotropic genetic influence on sensitivity to these drugs. [source]

Ethanol-Regulated Genes That Contribute to Ethanol Sensitivity and Rapid Tolerance in Drosophila

An Assay for Evoked Locomotor Behavior in Drosophila Reveals a Role for Integrins in Ethanol Sensitivity and Rapid Ethanol Tolerance

Sizing up Ethanol-Induced Plasticity: The Role of Small and Large Conductance Calcium-Activated Potassium Channels

ALCOHOLISM, Issue 7 2009
Patrick J. Mulholland
Small (SK) and large conductance (BK) Ca2+ -activated K+ channels contribute to action potential repolarization, shape dendritic Ca2+spikes and postsynaptic responses, modulate the release of hormones and neurotransmitters, and contribute to hippocampal-dependent synaptic plasticity. Over the last decade, SK and BK channels have emerged as important targets for the development of acute ethanol tolerance and for altering neuronal excitability following chronic ethanol consumption. In this mini-review, we discuss new evidence implicating SK and BK channels in ethanol tolerance and ethanol-associated homeostatic plasticity. Findings from recent reports demonstrate that chronic ethanol produces a reduction in the function of SK channels in VTA dopaminergic and CA1 pyramidal neurons. It is hypothesized that the reduction in SK channel function increases the propensity for burst firing in VTA neurons and increases the likelihood for aberrant hyperexcitability during ethanol withdrawal in hippocampus. There is also increasing evidence supporting the idea that ethanol sensitivity of native BK channel results from differences in BK subunit composition, the proteolipid microenvironment, and molecular determinants of the channel-forming subunit itself. Moreover, these molecular entities play a substantial role in controlling the temporal component of ethanol-associated neuroadaptations in BK channels. Taken together, these studies suggest that SK and BK channels contribute to ethanol tolerance and adaptive plasticity. [source]

Ethanol Tolerance Caused by slowpoke Induction in Drosophila

ALCOHOLISM, Issue 5 2006
Roshani.
Background: The large-conductance calcium-activated potassium channel encoded by the slowpoke gene has recently been implicated in the ethanol response. Caenorhabditis elegans carrying mutations in this gene have altered ethanol sensitivity and Drosophila mutant for this gene are unable to acquire rapid tolerance to ethanol or anesthetics. In Drosophila, induction of slowpoke expression has been linked to anesthetic resistance. Methods: We used Drosophila as a model system to examine the relationship between slowpoke expression and ethanol tolerance. Real-time PCR and a reporter transgene were used to measure slowpoke induction after ethanol sedation. An inducible slowpoke transgene was used to manipulate slowpoke levels in the absence of ethanol sedation. Results: Ethanol sedation increased transcription from the slowpoke neural promoters but not from the slowpoke muscle/tracheal cell promoters. This neural-specific change was concomitant with the appearance of ethanol tolerance, leading us to suspect linkage between the two. Moreover, induction of slowpoke expression from a transgene produced a phenotype that mimics ethanol tolerance. Conclusions: In Drosophila, ethanol sedation induces slowpoke expression in the nervous system and results in ethanol tolerance. The induction of slowpoke expression alone is sufficient to produce a phenotype that is indistinguishable from true ethanol tolerance. Therefore, the regulation of the slowpoke BK-type channel gene must play an integral role in the Drosophila ethanol response. [source]

Expression of c-Fos in Alko Alcohol Rats Responding for Ethanol in an Operant Paradigm

ALCOHOLISM, Issue 5 2001
Adam Z. Weitemier
Background: Identification of the brain regions involved in ethanol administration is important for understanding the neurobiology of ethanol addiction. Animal studies with different brain mapping techniques found that voluntary ethanol self-administration leads to changes in activity of specific brain regions in patterns that only partially overlap with patterns of brain regions affected by involuntary (i.e., experimenter-administered) ethanol administration. As an extension of studies mapping changes in neural activity after voluntary ethanol drinking, this study analyzed expression of the inducible transcription factor c-Fos after ethanol consumption in an operant procedure. Methods: AA (Alko alcohol) rats were trained to operantly respond for water, 0.2% saccharin, 0.2% saccharin/10% (w/v) ethanol, or 10% ethanol in a 30-min limited-access procedure. Animals were allowed to self-administer solutions for at least 40 ethanol response sessions and were killed 1.5 hr after beginning of the last session. Forty-seven brain regions were immunohistochemically analyzed for c-Fos expression. Results: In this paradigm, ethanol dose-dependently increased c-Fos expression in the Edinger-Westphal nucleus (EW) and decreased expression in the dorsal tenia tecta compared with no-ethanol controls. No effects of saccharin on c-Fos expression were found. Conclusions: Our results extend previous findings of preferential sensitivity of EW to alcohol in voluntary self-administration procedures to operant responding for ethanol and warrant further investigation of ethanol's effects on the EW. The finding that ethanol attenuated c-Fos expression in the tenia tecta is novel. Taken together, these findings confirm that voluntary ethanol self-administration leads to changes in activity of a limited number of brain regions with previously unexamined roles in ethanol sensitivity and addiction. [source]

Genetic Control of Acute Ethanol-Induced Behaviors in Drosophila

ALCOHOLISM, Issue 8 2000
Carol M. Singh
Background: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol. Methods: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol-induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure. Results: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol-induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol-induced turning behavior. Conclusions: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently. [source]

Differential Effects of Ethanol on Insulin-Like Growth Factor-I Receptor Signaling

ALCOHOLISM, Issue 2 2000
Andrea E.M. Seiler
Background: Activation of the insulin-like growth factor I receptor (IGF-IR) by its ligands IGF-I and IGF-II induces cell proliferation and protects against apoptosis. Ethanol inhibits IGF-IR tyrosine autophosphorylation, which subsequently interferes with the activation of key downstream signaling mediators including insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and mitogen-activated protein (MAP) kinase. The ethanol-induced inhibition of IGF-IR signaling reduces mitogenesis and enhances apoptosis. In the current study, we demonstrate that the antiproliferative action of ethanol can be modulated by differential sensitivity of the autophosphorylation of the IGF-IR to ethanol. Methods: A series of subclones was generated from 3T3 cells that express the human IGF-IR. Results: There was considerable variability in the ability of ethanol to inhibit IGF-I-dependent IGF-IR tyrosine autophosphorylation and MAP kinase activation, despite equivalent IGF-IR expression. The IGF-IR was completely resistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF-IR autophosphorylation to ethanol correlated directly with the inhibition of IGF-I-mediated MAP kinase activation and cell proliferation. Resistant subclones exhibited features of the transformed phenotype including high MAP kinase activity, partial loss of contact inhibition, and the development of foci at confluency. The IGF-IR isolated from ethanol-resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro, whereas ethanol inhibited the autophosphorylation of IGF-IR obtained from sensitive cells. Conclusions: Our findings are the first to demonstrate the modulation of ethanol sensitivity of a tyrosine kinase receptor, and they provide a molecular basis for differential effects of ethanol on cell proliferation. [source]