Conditioned Taste Aversions. Fig. 1. The balance between the rewarding and aversive affective properties of a drug influences total drug intake. When a drug of abuse is administered at low doses, the subjective effects are primarily rewarding (green-dashed line), leading to dose-dependent increases in drug intake or self-administration (blue-solid line). However, as the dose of the drug increases, aversive drug effects (red-dotted line) begin to influence the amount of drug self-administered (in their balance with the drug's rewarding effects), leading to lower levels of overall intake. The intensity of the aversive effects experienced during initial drug use impacts the probability of future drug taking. Changes in the aversive effects (resulting from experience with the drug or specific characteristics of the individual) impact a user's likelihood of subsequent use or abuse of the drug. This is based on a conceptualization by Greg Busse (2004).
protecting factor for continued use (Fig. 1). If this is the case, studying the various factors that can influence such aversive effects becomes just as important as studying the factors that can alter drug reward. CTA learning offers such a model in which the drug's aversive effects become paired with a distinctive flavor. In this case, changes in consumption (reductions) index the drug's aversive effects. The procedure also allows one to see how such effects vary with experimental manipulations and subject characteristics.
As noted, a variety of factors affect the likelihood of drug use and abuse. Some are specific manipulations such as dose of the drug and frequency of its use, while other factors are more characteristic of the user. A subject characteristic that is widely considered to be important in drug addiction is genetic predisposition or ► pharmacogenetics. One way that the genetic influence on drug abuse has been studied in the laboratory is through the use of selected or ► inbred rat strains, or mouse lines as ► animal models of particular aspects of the disease. An animal model that has received considerable attention in drug abuse research in recent years is that of the ► Fischer (F344)/Lewis (► LEW) ► inbred rat strains which show diverse drug intake and responsivity patterns across a number of drug classes (a review of genetic effects on CTA in rodents can be found in Riley et al. 2009). One among the drugs for which these strains show marked differences is alcohol. During oral self-administration studies, the LEW strain consumes greater amounts of alcohol than the F344 strain. However, it does not appear to be the case that the alcohol is more rewarding in LEW compared to F344, because both strains show comparable alcohol-induced
► conditioned place preferences, a model of
► conditioned drug effects sensitive to drug reward. Instead, the differences in alcohol consumption appear to be rooted in a differential sensitivity to the aversive effects of the drug. Specifically, F344 rats show greater suppression of saccharin drinking (i.e., a stronger CTA) when saccharin is paired with a dose of alcohol than the LEW strain (see Fig. 2). That alcohol is reinforcing in F344 rats is evidenced by acquisition of alcohol self-administration, yet their failure to exhibit the levels of intake seen in the LEW strain may be due to the aversive effects of the drug serving as a limiting factor in overall intake. The relation of CTA to drug self-administration is also exemplified in correlational analyses of these behaviors in various mouse strains with similar results. Using a number of genetically distinct mouse lines, it has been shown that the degree of alcohol-induced CTA is related to overall levels of alcohol intake such that the mouse lines that consume high levels of alcohol display little or no CTAs when an alcohol injection is paired with saccharin intake. Those mouse lines that drink very little alcohol are the ones that show the greatest levels of alcohol-induced taste aversion conditioning. Interestingly, mice that show the greatest levels of CTA also show greater severity of alcohol withdrawal, suggesting an overall increased sensitivity to the aversive effects produced by alcohol. The oral self-administration of alcohol appears unrelated to the acquisition of alcohol-induced place preferences in these strains, suggesting that the differences in alcohol self-administration are mediated more by differences in alcohol aversion than alcohol reward. While we have chosen to focus on alcohol, parallel effects with the F344/LEW model, in particular, are evident with a diverse range of drug classes and include compounds such as morphine, ► nicotine, and cocaine. Further, a variety of parameters other than strains, for example drug history, dose of the drug, route of administration, age, and sex have been shown to impact taste aversion learning (see Riley and Freeman 2004) as well as drug self-administration (see Schuster and Thompson 1969) in related ways, suggesting
Conditioned Taste Aversions. Fig. 2. Dose effect of alcohol-induced conditioned taste aversions (CTA) in the Fischer (F344) and Lewis (LEW) rat strains. Both strains show dose-dependent reductions (from vehicle-treated rats) in saccharin consumption when alcohol (injected intraperitoneally) followed saccharin. However, the F344 strain displays a greater sensitivity to the aversive effects compared to the LEW strain. Interestingly, LEW rats consume greater amounts of an available alcohol solution (per body weight) than F344 rats, suggesting that the greater sensitivity to the aversive effects limits alcohol intake in the F344 strain. Conversely, the LEW strain, which shows weak CTAs, may be more vulnerable to greater alcohol consumption because of their apparent insensitivity to its aversive effects. (Figure redrawn from Roma et al. 2006.)
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