We explored changes that occur during the acquisition of heroin self-administration in rats. To achieve this, we assessed responses made during the time of a drug infusion (unreinforced responding) throughout the acquisition of intravenous heroin and studied other behavioral effects of heroin during this period. We compared heroin to cocaine self-administration and responding for sucrose. Unreinforced responding developed in rats lever-pressing for heroin and sucrose, but not for cocaine. Unreinforced responding increased with food-deprivation in sucrose experiments, and decreased in heroin experiments following an injection of heroin. Locomotor activity and the rewarding properties of heroin increased during acquisition and maintenance of heroin self-administration. This evidence suggests that unreinforced responding reflects both a change in the animal's motivation to obtain the drug and a reduced sensitivity to side-effects of the drug. These data contribute to our understanding of factors that regulate transition from drug use to drug abuse and eventually, dependence.