Nicotine has been shown to maintain intravenous self-administration behaviour in humans and laboratory animals. However, factors critical in the initiation of nicotine self administration are not well defined. In particular genetic differences and effects of pre-exposure to nicotine have not been examined. Male Sprague-Dawley or Long-Evans rats were surgically prepared with indwelling jugular catheters and 3 days later received chronic injections of nicotine (0.4 mg/kg SC) or vehicle (saline, 1 ml/kg) for 7 days in their home cage. The next day, 2-h daily test sessions were initiated, during which rats were given the opportunity to nose-poke for nicotine infusions (0.015, 0.03 or 0.06 mg/kg per infusion) under a one-response fixed-ratio (FR-1) schedule of reinforcement with a 20-s time out after each infusion. One hole was defined as active while pokes in the other hole were recorded but had no scheduled consequence. The response requirement was increased progressively to five (FR-5) over successive sessions. Both saline- and nicotine-pretreated Sprague-Dawley rats showed a preference for the active hole, while only the saline-pretreated Long-Evans rats acquired the self-administration as defined by significant differences between responding in the active versus the inactive holes. The Fisher (F344) and Lewis inbred strains also failed to acquire self-administration of nicotine under these conditions. With Sprague-Dawley and Long-Evans rats that acquired the self-administration, and showed stable levels of maintained responding for nicotine, substituting saline for the nicotine or pretreating with mecamylamine (2.0 mg/kg SC) extinguished the behaviour. When dose per infusion was varied, an inverted U-shaped dose-response curve was obtained. These results support previous reports that nicotine can serve as a reinforcer in rodents and demonstrate that environmental factors such as prior nicotine exposure or genetic factors such as rat strain can affect acquisition of nicotine self-administration.