Rats were pretreated with nine daily injections of either d-amphetamine SO4(1.0 mg/kg, 1P), nicotine bitartrate (0.6 mg base/kg, SC) or saline. The motor activating effects of these drugs were measured for 60 min postinjection. On the tenth day, they were given a challenge injection of cocaine HCl (10 mg/kg) or saline and activity was again measured for 60 min postinjection. Both amphetamine and nicotine enhanced motor activity, although the stimulating effect of nicotine was not apparent until the third exposure to the drug. When the response to cocaine was assessed in these pre-exposed rats, only the amphetamine-treated animals were sensitized; they demonstrated a greater cocaine-induced motor activation than their saline-pretreated counterparts. The nicotine pre-exposed rats failed to demonstrate sensitization to the behavioral effect of cocaine; their response was not greater than the rats that had received pre-exposure to saline. These data demonstrate that the response to cocaine can be influenced by prior drug experience and that the influence may be dependent on the neurochemical specificity of the drug.