Browsing by Subject "Selective breeding"

Now showing 1 - 7 of 7
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    Chronic free-choice drinking in crossed HAP (cHAP) mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage
    (Wiley, 2013-02) Matson, Liana; Liangpunsakul, Suthat; Crabb, David; Buckingham, Amy; Ross, Ruth Ann; Halcomb, Meredith; Grahame, Nicholas; Department of Psychology, School of Science
    Background Crossed High Alcohol Preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines, and demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP 2E1) induction plays a prominent role in driving both metabolic tolerance and ethanol-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an ethanol liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In Experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of ethanol accumulation in these mice. In Experiments 1 and 2, mice were injected with ethanol following 3–4 weeks of access to water or 10% ethanol and water, and blood samples were taken to assess metabolic tolerance. In Experiment 3, 24 mice had 4 weeks access to 10% ethanol and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points, and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, ethanol-exposed mice metabolized ethanol faster than ethanol-naïve mice, demonstrating metabolic tolerance (p < .05). In experiment 3, ethanol-drinking mice showed greater expression of hepatic CYP 2E1 than water controls, consistent with the development of metabolic tolerance (p < .05). Ethanol access altered neither hepatic histology nor levels of ADH and ALDH. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2E1 induction. Together these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.
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    Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings
    (Elsevier, 2016) Bell, Richard L.; Hauser, Sheketha R.; McClintick, Jeanette; Rahman, Shafiqur; Edenberg, Howard J.; Szumlinski, Karen K.; McBride, William J.; Department of Psychiatry, IU School of Medicine
    Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.
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    From QTL to candidate gene: a genetic approach to alcoholism research
    (Bentham Science, 2009-05) Spence, John P.; Liang, Tiebing; Liu, Lixiang; Johnson, Philip L.; Foroud, Tatiana; Carr, Lucinda G.; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), alpha-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.
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    The neurobiology of alcoholism in genetically selected rat models
    (The National Institute on Alcohol Abuse and Alcoholism, 1997) Stewart, Robert B.; Li, Ting-Kai; Psychology, School of Science
    Rats selectively bred for their tendency to drink large or small quantities of alcohol are a useful model for investigators examining the possible neurobiological processes underlying alcoholism. Studies with the alcohol-preferring (P) and alcohol-nonpreferring (NP) and the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) pairs of rat lines developed at Indiana University have illustrated differences in several behavioral and neurobiological characteristics associated with alcohol consumption. Specifically, compared with alcohol-avoiding rats, rats with an affinity for alcohol have a greater sensitivity to the stimulatory effects of low to moderate doses and a reduced sensitivity to the negative effects of high doses. Rats that voluntarily drink large quantities of alcohol also acquire tolerance to alcohol’s aversive effects. In addition, these rats differ from their alcohol-avoiding counterparts in the levels of several chemical mediators (i.e., neurotransmitters) found in the brain, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and the endogenous opioids.
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    Quantitative trait locus for body weight identified on rat chromosome 4 in inbred alcohol-preferring and –nonpreferring rats: potential implications for neuropeptide Y and corticotrophin releasing hormone 2
    (Elsevier, 2013) Spence, John Paul; Lai, Dongbing; Shekhar, Anantha; Carr, Lucinda G.; Foroud, Tatiana; Liang, Tiebing; Psychiatry, School of Medicine
    The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed using bidirectional selective breeding for alcohol consumption (g/kg/day) and alcohol preference (water:ethanol ratio). During a preliminary study, we detected a difference in body weight between inbred P (iP) and inbred NP (iNP) rats that appeared to be associated with the transfer of the Chromosome 4 quantitative trait locus (QTL) seen in the P.NP and NP.P congenic strains. After the initial confirmation that iP rats displayed lower body weight when compared to iNP rats (data not shown), body weight and growth rates of each chromosome 4 reciprocal congenic rat strain (P.NP and NP.P) were measured, and their body weight was consistent with their respective donor strain phenotype, confirming that a quantitative trait locus for body weight mapped to the chromosome 4 interval. Utilizing the newly developed interval-specific congenic strains (ISCS-A and ISCS-B), the QTL interval was further narrowed identifying the following candidate genes of interest: neuropeptide Y (Npy), juxtaposed with another zinc finger gene 1 (Jazf1), corticotrophin releasing factor receptor 2 (Crfr2) and LanC lantibiotic synthetase component C-like 2 (Lancl2). These findings indicate that a biologically active variant(s) regulates body weight on rat chromosome 4 in iP and iNP rats. This QTL for body weight was successfully captured in the P.NP and NP.P congenic strains, and interval-specific congenic strains (ISCSs) were subsequently employed to fine-map the QTL interval identifying the following candidate genes of interest: Npy, Jazf1, Crfr2 and Lancl2. Both Npy and Crfr2 have been previously identified as candidate genes of interest underlying the chromosome 4 QTL for alcohol consumption in iP and iNP rats.
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    Rat strain differences in brain structure and neurochemistry in response to binge alcohol
    (Springer, 2014-01) Zahr, Natalie M.; Mayer, Dirk; Rohlfing, Torsten; Hsu, Oliver; Vinco, Shara; Orduna, Juan; Luong, Richard; Bell, Richard L.; Sullivan, Edith V.; Pfefferbaum, Adolf; Psychiatry, School of Medicine
    RATIONALE: Ventricular enlargement is a robust phenotype of the chronically dependent alcoholic human brain, yet the mechanism of ventriculomegaly is unestablished. Heterogeneous stock Wistar rats administered binge EtOH (3 g/kg intragastrically every 8 h for 4 days to average blood alcohol levels (BALs) of 250 mg/dL) demonstrate profound but reversible ventricular enlargement and changes in brain metabolites (e.g., N-acetylaspartate (NAA) and choline-containing compounds (Cho)). OBJECTIVES: Here, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats systematically bred from heterogeneous stock Wistar rats for differential alcohol drinking behavior were compared with Wistar rats to determine whether genetic divergence and consequent morphological and neurochemical variation affect the brain's response to binge EtOH treatment. METHODS: The three rat lines were dosed equivalently and approached similar BALs. Magnetic resonance imaging and spectroscopy evaluated the effects of binge EtOH on brain. RESULTS: As observed in Wistar rats, P and NP rats showed decreases in NAA. Neither P nor NP rats, however, responded to EtOH intoxication with ventricular expansion or increases in Cho levels as previously noted in Wistar rats. Increases in ventricular volume correlated with increases in Cho in Wistar rats. CONCLUSIONS: The latter finding suggests that ventricular volume expansion is related to adaptive changes in brain cell membranes in response to binge EtOH. That P and NP rats responded differently to EtOH argues for intrinsic differences in their brain cell membrane composition. Further, differential metabolite responses to EtOH administration by rat strain implicate selective genetic variation as underlying heterogeneous effects of chronic alcoholism in the human condition.
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    Selected lines and inbred strains. Tools in the hunt for the genes involved in alcoholism
    (The National Institute on Alcohol Abuse and Alcoholism, 2000) Grahame, Nicholas J.; Medicine, School of Medicine
    In their quest to elucidate the genetic influences contributing to alcoholism, researchers have long used selected lines and inbred strains of rodents. Selected lines are obtained by repeatedly mating those animals within a population that show extremely high or low values of the desired trait. Inbred strains are generated by mating male and female siblings, irrespective of any particular trait, over several generations. Both of these approaches have provided researchers with extensive knowledge about the genetic and neurobiological mechanisms contributing to alcohol-related traits. However, the use of these models is associated with some limitations, mostly resulting from the inbreeding involved in generating such lines and strains. Nevertheless, these models can offer some advantages over other genetic approaches, such as the analysis of quantitative trait loci or the generation of transgenic and knockout mice.