The essential role of the amygdala in learning and memory, including cue-associated learning, is influenced by local release of norepinephrine (NE). The current study investigated changes in amygdaloid NE secretion in rats learning to self-administer nicotine in an unlimited access model (23 h/day). In vivo microdialysis of NE was performed for 9 h intervals during three phases of nicotine self-administration: acquisition (day 1); early maintenance, when self-administration rates first stabilized (day 8.4+/-0.7); and later, during fully stable maintenance (day 17.6+/-1.0). On day 1, a greater number of self-administration episodes (SAEs) were associated with elevated NE levels in rats bar-pressing for nicotine (88% vs. 39% with saline). By early maintenance, such episodes increased threefold and overall NE levels were greater. During later maintenance, however, bar-pressing behavior was similar and NE was elevated by the first SAE of the day, but total daily NE levels were no longer elevated. In all the three phases, the enhanced NE release during the first daily SAE did not occur in the last SAE 9 h later. Thus, in an animal model of unlimited nicotine self-administration that approximates the human pattern of nicotine consumption via smoking, the amygdaloid NE response to nicotine diminishes over each day and with the stabilization of self-administration. The decline of amygdaloid NE secretion after long-term nicotine self-administration likely reflects desensitization to the pharmacological effects of nicotine. In addition, amygdaloid NE release, which enhances the consolidation of amygdala-dependent memory, may no longer be necessary once self-administration behavior has been established.