Various animal models of nicotine dependence now exist. To study the positive reinforcing effects of nicotine, there are choices of animal species, strains, and operant paradigms to use. This manuscript describes the use of one particular paradigm, a model in which work is done by laboratory animals to obtain intravenous infusions of nicotine. This model is particularly useful for examining the mechanisms in the brain that are responsible for the maintenance of drug-taking behavior. Two examples of ongoing studies of the mechanisms of dependence are discussed: the role of cholinergic projections to midbrain dopamine cells, and the influence of opioid receptors in the vicinity of these same dopamine cells.