Addiction is a major problem in the United States. In addition to the numerous economic and legal repercussions on society, drugs of abuse also produce devastating effects in the individual. One such consequence of continued drug use is a devaluation of the natural rewards encountered in the environment. For example, people with a history of cocaine use and even smokers who are expecting a chance to smoke in the immediate future have been found to be less sensitive to monetary reward (Goldstein et al., 2008; Wilson et al., 2008). Similarly, drug addicts tend to develop a generalized insensitivity to food and social relationships and it has been shown that addicts are more likely to weigh less, to lose their jobs, and to have their children removed from their home due to neglect (Jones et al., 1995; Santolaria-Fernandez et al., 1995; Nair et al., 1997).

A contributing factor in the devaluation of natural rewards by drugs of abuse is the principle of incentive relativity. Incentive relativity states that rewards are not evaluated in a vacuum (i.e., the value of a given reward is not determined only by its intrinsic value), but also by its relative value in comparison with other rewards. Such comparisons, however, normally occur between natural rewards found in the environment in a relatively plastic manner. When natural rewards are evaluated against artificially intense drugs of abuse, these lesser natural rewards can become devalued and are subsequently avoided.

Given that this effect of drugs of abuse on natural rewards is influenced by the comparison of rewards, individual or group differences in reward preference and/or sensitivity, both innate and relative, may play an important role in the devaluation of natural rewards observed in drug addiction. To date, however, this aspect of drug addiction has remained largely unexplored. The goal of the current thesis was to use rat and mouse strains with differential preference for rewards to evaluate the effect of differences in sensitivity to rewards in a rodent model of drug-induced devaluation of natural rewards. Although increased reward preference was found to facilitate drug-induced suppression of a reward cue in rats in Chapter 2, and this facilitation extended to comparisons between disparate natural sweet rewards in Chapter 3, the suppressive effect of drug on reward intake was attenuated in reward-preferring mice in Chapter 4. This attenuated effect in ‘reward sensitive’ strains of mice was not due to differences in impulsivity and was shown, with the use of transgenic ΔFosB mice in Chapter 5, to be associated with an increased sensitivity to not only drug, but also to the natural reward cue. Indeed, when the natural reward cue was switched from sweet to bitter in Chapter 6, the strain effect was eliminated. Taken together, the data in this dissertation suggest that a single substrate, ultimately, can mediate sensitivity to drugs of abuse and natural rewards. Thus, while natural reward cues can predict drug availability and can, in so doing, be devalued, strong natural rewards also can blunt the rewarding impact of a drug of abuse and, thereby, responding for a drug of abuse and the ensuing development of addiction.