Rodent models of genetic contributions to motivation to abuse alcohol

Abstract

In summary, there are remarkably few studies focused on the genetic contributions to alcohol's reinforcing values. Almost all such studies examine the two-bottle preference test. Despite the deficiencies I have raised in its interpretation, a rodent genotype's willingness to drink ethanol when water is freely available offers a reasonable aggregate estimate of alcohol's reinforcing value relative to other genotypes (Green and Grahame 2008). As indicated above, however, preference drinking studies will likely never avoid the confounding role of taste preferences and most often yield intake levels not sufficient to yield a pharmacologically significant BAL. Thus, the quest for improved measures of reinforcing value continues. Of the potential motivational factors considered by McClearn in his seminal review in this series, we can safely conclude that rodent alcohol drinking is not primarily directed at obtaining calories. The role of taste (and odor) remains a challenge. McClearn appears to have been correct that especially those genotypes that avoid alcohol are probably doing so based on preingestive sensory cues; however, postingestive consequences are also important. Cunningham's intragastric model shows the role of both preingestional and postingestional modulating factors for the best known examples, the usually nearly absolutely alcohol-avoiding DBA/2J and HAP-2 mice. Much subsequent data reinforce McClearn's earlier conclusion that C57BL/6J mice, at least, do not regulate their intake around a given self-administered dose of alcohol by adjusting their intake. This leaves us with the puzzle of why nearly all genotypes, even those directionally selectively bred for high voluntary intake for many generations, fail to self-administer intoxicating amounts of alcohol. Since McClearn's review, many ingenious assays to index alcohol's motivational effects have been used extensively, and new methods for inducing dependence have supplanted the older ones prevalent in 1968. I have tried to identify promising areas where the power of genetics could be fruitfully harvested and generally feel that we have a much more clear idea now about some important experiments remaining to be performed.

Figure 2.1

Daily preference ratio of consumed 10% alcohol solution/total fluid consumption. Data for 4 individual male mice per genotype are shown. Broken vertical lines between Days 6–7 and 10–11 indicate reversal of position of alcohol and water solutions. Adapted from Figure 1 in McClearn & Rodgers (1959), with permission.

Figure 2.2

Correlations among means of inbred strains observed in different laboratories. The dashed line indicates what would be identical results for two laboratories, and the gray line is the best fit regression of data from the y axis to data on the x axis, plotted for the actual range of data. Numbers 1–30 correspond to inbred mouse strains. Effect sizes from the ANOVAs are shown for the strain main effect and strain-by-laboratory interaction as insets within each panel. The significance (P) of the interaction effect is also indicated. NS denotes an interaction not significant at P # 0.05. (A) Brain weight measured in the Edmonton laboratory versus four other laboratories. (B) Preference ratios for two bottle ethanol preference tests conducted in 4 laboratories. Adapted from Figure 1 in Wahlsten et al (2006), with permission.

Figure 2.3

Percentage of subjects with blood alcohol levels greater than 100 mg/dl (1.00 mg/ml) at the end of 4 hr of drinking 20% ethanol on Day 2 of the Drinking in the Dark test. The horizontal bar indicates 50%. Approximately 50–120 mice were tested each generation, and data are collapsed on sex. Selection of the HDID-1 line was initiated 7 generations before the initiation of the HDID-2 line. For details of the selection procedures, see Crabbe et al (2009).

Figure 2.4

Rapid tolerance to ingested alcohol in HDID-1 mice. Foot slip errors on the balance beam are shown for two pretraining days and three days when the animals were tested immediately after drinking 20% ethanol for 4 hr in the drinking in the dark test. Average dose of ethanol consumed is shown for each day. The bar indicates the difference between errors on Days 1 and 3, corrected for average baseline foot slips on pretraining days 1 and 2. Means “ SE are shown.