Browsing by Author "Grahame, N.J."

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    ACUTE FUNCTIONAL TOLERANCE TO ETHANOL IN MICE SELECTIVELY BRED FOR HIGH AND LOW ALCOHOL PREFERENCE DRINKING
    (Office of the Vice Chancellor for Research, 2012-04-13) Fritz, B.M.; Grahame, N.J.; Boehm II, S.L.
    Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of the current study was to assess this potential corre-lated response in second and third replicate lines of mice selectively bred for high (HAP2&3) and low (LAP2&3) alcohol preference drinking. We predicted that HAP mice would develop greater AFT to alcohol’s ataxic actions than LAP mice. Male and female HAP2&3 and LAP2&3 mice were tested for development of AFT on a static dowel task. This task requires that animals maintain balance on a wooden dowel in or-der to prevent falling. On test day, each mouse received one (1.75g/kg; experiment 1) or two (1.75g/kg and 2.0g/kg; experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in another experiment, an additional administration after the first regain of balance on the dowel. Blood samples were tak-en immediately after loss of balance and regain in Experiment, 1 and after first and second regain in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BACs than LAP mice following the initial injection of ethanol and were therefore more sensitive. Furthermore, the single-injection experiment detected significantly greater AFT development (BAC2-BAC1) in HAP mice as compared to LAP mice, supporting our hypothesis. This study illus-trates the rapidity with which adaptive pharmacodynamic processes can take place which may contribute to excessive alcohol consumption.
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    Impulsivity and Alcohol Drinking in an Animal Model of Alcoholism
    (Office of the Vice Chancellor for Research, 2010-04-09) Grahame, N.J.; Oberlin, B.O.; Bristow, R.E.; Heighton, M.E.
    Alcoholism is a widespread problem, and although we are beginning to characterize genes that mediate its heritable nature, we still do not understand how a family history of alcoholism places individuals at risk for this disorder. One trait that is consistently elevated, both in alcoholics and those who suffer from a variety of addictive disorders, is impulsivity. Impulsivity can be defined as a self-defeating tendency to choose immediate, but small rewards over large rewards given at following a delay. Normally, instituting a delay to a reward decreases its subjective value, a phenomenon called delay discounting. In alcoholics, the slope of this decline in value as a function of time is steeper than in non-drinkers, but it has been difficult to demonstrate in humans whether this results from a lifetime of drinking, or causes problem drinking in the first place. In the present studies we utilized an animal model of alcoholism, the selectively bred High Alcohol Preferring (HAP) mouse, comparing them to Low Alcohol Preferring (LAP) mice as well as non-selected, outbred mice using the translational measure of impulsivity, delay discounting. By using alcohol naïve mice, we were able to assess whether genes promoting alcohol drinking increase impulsivity without the potential confound of a history of alcohol exposure. In follow-up studies, we assessed whether pharmacotherapies for alcoholism decrease impulsivity as well as alcohol consumption in HAP mice. Alcohol naïve HAP, LAP, and HS/Ibg mice were subjected to a saccharin-motivated delay discounting procedure in which the value of an immediate reward was titrated until it was subjectively equivalent to a delayed reward. As expected, time to the delayed reward decreased its value, and did so more steeply in HAP mice than in LAP and unselected HS/Ibg mice, supporting the hypothesis that impulsivity plays a causal role in initiating high drinking behavior. In related studies, we assessed whether two pharmacotherapies for alcoholism, memantine (an NMDA antagonist) and naltrexone (an opioid antagonist), altered delay discounting behavior and (in separate mice) alcohol drinking. Although these two drugs decreased free-choice drinking in HAP mice, consistent with their beneficial effects on alcoholism, they did not alter impulsivity. Amphetamine, a general dopamine agonist with known anti-impulsive actions, decreased impulsivity in HAP mice, but did not alter alcohol consumption in a behaviorally selective manner. These findings support a role for impulsivity in the development of alcoholism, but leave unanswered the question of which neural systems would serve as the best pharmacological targets for the development of medications aimed at treating those with, or at a high risk for, alcoholism.