Issues in Controlled Substance Use Papers and Commentary, Conference on Issues in Controlled Substance Use (1980) / Chapter Skim
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Animal Models as Pharmacogenetic Tools: Some Initial Explorations Into Alcohol Consumption
Animal Models as Pharmacogenetic Tools: Some Initial Explorations Into Alcohol Consumption
Pages 142-189
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From page 142... ...
Our first study compared several inbred mouse strains in a two-bottle choice situation in which the animals could choose between tap water and a l0-percent ethanol solution. The daily intake from each bottle was recorded for each mouse for a period of two weeks.
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From page 143... ...
It is not unusual, as in the example shown in Figure 2, to find an occasional abstaining C57BL mouse, at least when observations are made only for a two-week period. Most alcohol preference data on C57BL animals have been obtained during two-week observation periods, and the mean consumption has been found to increase from about 50 percent of the total fluid intake to 80 percent or more in that length of time.
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From page 144... ...
The mean alcohol preference ratios of these groups were 0.4l, 0.37, and 0.l3, respectively. More extensive observations on animals from 3 weeks of age through 20 weeks have given clear indication that alcohol preference of young BALB/c animals greatly exceeds that of adults (Kakihana and McClearn, l963)
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From page 145... ...
Whether such changes in alcohol intake are initiated by endogenous events or triggered by external stimuli, they would seem to offer opportunities for elucidating the mechanisms of alcohol intake regulation through studies of the physiological correlates of the changes. THE ETHANOL INTAKE CONTROL SYSTEM OF C57BL MICE The existence of intermediate levels of ethanol consumption in various strains and the fact that even C57BL mice do not drink exclusively from the ethanol solution indicate that the mechanism for controlling ethanol intake does not simply determine acceptance or avoidance.
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From page 146... ...
An examination of the solid line in the preshift portion of Figure 9 shows that the absolute amount of ethanol ingested increased from 3 percent through l2 percent with a subsequent drop at 24 percent. The line separating the cross-hatched from the stippled areas of the figure represents the total volume of ethanol solution consumed (i.e., absolute amount of ethanol plus the water from the ethanol solution)
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From page 147... ...
Lines representing total liquid, volume of ethanol solution, and absolute amount of ethanol consumed are drawn through the means at each point. Although there is a general consistency of results for the different shifted and control groups with respect to the total liquid measure and the ethanol solution measure, the most remarkable uniformity is found for the ethanol amount measure.
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From page 148... ...
were followed. Under the 5-percent choice condition, the mean absolute amount of ethanol ingested over the nine days was l.l4 ml; under the l0-percent condition, it was 2.l8 ml; and under the 20-percent condition, it was 2.38 ml.
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From page 149... ...
PC designates a position change of the ethanol solution and water bottles, and INJ signifies injection. It should be noted that 0.5 cc of a 20-percent solution would equal l.0 cc of a l0-percent solution in terms of absolute amount of ethanol.
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From page 150... ...
could be used to increase daily fluid intake, but we chose the simple strategem of adding sucrose to both the water and the ethanol solution. C57BL males, approximately l36 days of age when the experiment began, were presented with the standard two-bottle choice between tap water and l0-percent ethanol solution for l5 days.
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From page 151... ...
Therefore, the relationship between strain means for alcohol preference and strain means for alcohol dehydrogenase (ADH) activity was plotted, and a positive relationship was found.
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From page 152... ...
, display a reduced alcohol preference. Are there implications from what is known of the physiological functioning of the albino gene for our description of the EICS?
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From page 153... ...
and ethanol acceptance. Thus, while the result confirms in a general way that there may be some influence of enzyme activity on ethanol consumption, only about 8 percent of the variation in the latter is "explainable" in terms of variation in the former.
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From page 154... ...
Differences in alcohol preference among inbred strains of mice. Quarterly Journal of Studies on Alcohol 20:69l-695.
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From page 155... ...
(l963) Genetic and biochemical determinants of alcohol preference and alcohol metabolism in mice.
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From page 156... ...
>_._.-^^ " i . : ^ » 1 4 i i I III "K=CC-' j^ NjJ: llii Kl 0 K O I 1 1 c _ .- o i- 3 .c *
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From page 157... ...
Frequency distributions of mean preference ratios (ratio of consumed alcohol solution to total consumed liquid during a two-week period) for three inbred mouse strains.
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From page 158... ...
-.i- J.-_L._L 9 l1 13 Week 15 17 19 Figure 3. Mean weekly preference ratios of male C57BL mice offered a choice between tap water and l0 percent ethanol solution (0-l0 group)
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From page 159... ...
. Development of alcohol preference in BALB/c mice.
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From page 160... ...
. Development of alcohol preference in BALB/c mice.
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From page 161... ...
Mean preference ratios of individual BALB/c mice that displayed episodes of high alcohol intake during a l50-day observation period.
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From page 162... ...
Mean preference ratios of individual C57BL mice that displayed changes in alcohol intake during a 200-day observation period.
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From page 163... ...
n i Total Liquid I OO OO -- cvj -- cvj OO OO -- cvjevj OO OO OO OO -- -- cvjcvj -- cvj -- cvj Absolute Amount Ethanol (read ordinate in ml.) I Q 00 oo oo oo oo oo oo oo -- cvj -- cvj cvjcvj -- cvj -- cvj cvjcvj 1 i i i i i i i i i i i i i i i OO OO OO OO OO OO OO OO cvjcvj -- cvj -- cvi cvjcvj -- cvj -- cvj OO 00 00 OO -- cvj -- cvj cvjcvj ii ii ii ii OO OO OO OO CVJCVJ -- cvj -- cvj Figure 8.
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From page 164... ...
Liquid consumption measures for male C57BL mice offered a choice between tap water and various concentrations of ethanol solution during preshift and postshift periods as described in the text. Source: McClearn, G.E.
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From page 165... ...
l65 § o S ^ o in A e tn 0> O Preshift • Postsh.-t 1.5 3 6 Concentration 12 24 Figure l0. Absolute amount of ethanol consumed by male C57BL mice as a function of concentration of the ethanol solution during preshift and postshift periods as described in the text.
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From page 166... ...
Liquid consumption measures for male C57BL mice as a function of concentration of ethanol solution and previous experience. In the postshift results, the circled numbers identify the mean levels of the various groups currently being tested at the concentration shown on the abscissa.
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From page 167... ...
PC designates a position change of the ethanol solution and water bottles; INJ signifies injection.
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From page 168... ...
Mean consumption of l0 percent ethanol solution by C57BL mice before, during, and after six days of forced alcohol consumption. Source: McClearn, G.E.
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From page 169... ...
and after (Period II) the addition of sucrose to both the water and the ethanol solution.
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From page 170... ...
sugar^ II PERIOD Figure l5. Mean consumption of tap water and l0 percent ethanol solution by male, 52-day-old C57BL mice under conditions comparable to those described for Figure l4.
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From page 171... ...
12 II 10 9 8 o° o co 5 ec UJ §4 2 I 0 T -Tw ,s W- WATER A - ALCOHOL 8-8UOM T- TOTAL GROUP A 345678 BLOCKS OF 3 DAYS 10 Fiqure l6 Mean li(1uid consumption measures for male, 52-day-old C57BL mice in a group treated as described for Figure 14 (Group A)
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From page 172... ...
Ultimately, we must learn how life history variation and biological variation interact. I want to take up first Professor McClearn's points that behavioral variables that could be employed in evaluating a response to a drug are manifold, and seemingly related or similar behaviors or biological indices, such as enzyme activity, often turn out to be statistically independent.
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From page 173... ...
But again, for alcohol preference, alcohol acceptance, etc., there are a number of different situations that one could imagine or devise to evaluate such processes, and they're likely to give different results. It is attractive, at least, to imagine that underlying a complex of variables like this there may be some sort of behavioral, biological, or psychological reality.
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From page 174... ...
If you are selectively breeding for alcohol preference or alcohol acceptance you can in each generation or every third generation or so examine some of the animals for sleeping time. (For a more complete discussion, see G
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From page 175... ...
Consider an attribute like acetaldehyde dehydrogenase activity in the liver. (Well, that's a little problematic because you have to sacrifice one animal to get the alcohol dehydrogenase activity.
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From page 176... ...
In particular, the paper outlines some experiments that deal with a possible alcohol intake control system by which these animals limit the amount of ethanol they consume when placed into a two-bottle free-choice situation. He also discussed some of the possible mechanisms that might mediate genetically determined differences in alcohol preference behavior.
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From page 177... ...
Quite naturally, this raises the question of whether this research tells us anything about human alcohol consumption, particularly about the etiology of human alcoholism. One similarity between alcohol preference behavior in animals and human alcoholism is the fact that in animals the behavior is determined in part by genetic factors and there now exists a substantial literature to suggest that this may also be the case in human beings.
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From page 178... ...
Such experiments do not prove this point, but in any event it is at least possible that both animals and human beings inherit the propensity to drink alcohol from their parents. Another important question in pharmacogenetic studies of alcohol preference is how one thinks of preference and avoidance.
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From page 179... ...
However, we also observed an increase in total liver proteins in the animals that had experience with ethanol. Therefore it seemed possible that the increase in liver alcohol dehydrogenase activity that we had observed was merely a secondary reflection of the total increase in liver protein.
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From page 180... ...
In neither case do we know whether the increase in alcohol dehydrogenase activity represents true enzyme induction, but experiments that would allow us to answer this question are certainly possible with animal subjects. In summary, McClearn's experiments represent an attempt to understand genetically determined individual differences in alcohol preference behavior in inbred and selectively bred mice.
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From page 181... ...
Aldehyde dehyrogenase and ethanol preference in mice. Journal of Biological Chemistry 6l:l65-l69.
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From page 182... ...
The model was not presented in a nature-versus-nurture dichotomy, but rather as a genetically determined baseline on which environmental influences can act. Using inbred strains of mice, McClearn and colleagues developed strains with consistent relatively high preference for alcohol.
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From page 183... ...
McClearn pointed out that the low-preference mice showed aversion to alcohol with no prior exposure to its taste or effects. It was then pointed out that there are enormous individual variations not only in drug responses but in most responses to bacteria and viruses and in reactions to all environmental toxins studied.
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