Passive administration of nicotine activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system. However, little is known about the effects of self-administered nicotine. Drug-naive rats were trained to respond for food reinforcement and then tested in one, 1-h session in which they received response-contingent i.v. nicotine or response-independent i.v. nicotine or saline. Blood draws were taken immediately prior to the session, 15 min after the first infusion and immediately after the session. Both response-contingent and response-independent nicotine (RI/N) increased corticosterone within 15 min, however, corticosterone levels returned to baseline in animals receiving response-contingent nicotine (RC/N) by the end of the session while remaining elevated in those receiving RI/N. Furthermore, only RI/N increased plasma epinephrine and norepinephrine levels; RC/N produced no effect. These differences indicate that nicotine's acute effects are powerfully modified by the presence of a contingency relationship between drug administration and the animal's behavior and that this relationship develops very rapidly.