An extended history of drug self-administration results in multiple sources of control over drug seeking behavior.

It is widely recognized that across the development of drug addiction, cues associated with drug use come to exert increasing control over drug seeking and taking behaviors. However, there remain gaps in our knowledge regarding how the different types of drug related cues affect drug seeking and taking behaviors, and how the emergence of cue control over these behaviors relates to the onset of drug seeking compulsions. This paper reviews the literature on drug self-administration in animals to address these gaps. It first identifies the different types of cues that acquire control over reward seeking behavior generally, and examines whether the same types of cues acquire control over drug seeking behavior specifically. It then examines how the role of drug related cues in motivating and reinforcing drug seeking behavior changes across an extended drug-taking history, with a particular focus on the case of nicotine. The evidence reviewed shows that, after an extended history of drug taking, drug seeking behaviors are controlled by contextual cues associated with the development of drug seeking habits, response contingent cues that accompany delivery of the drug, as well as internal states that correlate with levels of drug intake. These multiple sources of control over drug seeking are discussed in relation to the generation of an addicted phenotype in animal models and the hypothesized progression from internal control over drug use to compulsive drug seeking.