Desensitization of norepinephrine release was investigated with repeated intravenous (i.v.) infusions of nicotine and in vivo microdialysis of the hippocampus. At 100 min intervals, rats received three infusions of one of the following doses of nicotine: 0.045, 0.09 or 0.135 mg/kg. Doses of 0.09 mg/kg or higher increased norepinephrine release (F= 2.41, P < 0.05). However, the norepinephrine response to the second or third infusion was significantly reduced, compared to the first. The extent of desensitization and rate of resensitization was investigated further by administering consecutive infusions of nicotine (0.135 mg/kg) 40, 60, 100 or 200 min apart. Less norepinephrine was released after a second nicotine infusion given 40 to 100 min later, but this was not reduced further by a third infusion. Norepinephrine release was unchanged with a 200 min inter-infusion interval. Therefore, in the hippocampus, maximal desensitization of nicotine-stimulated norepinephrine release occurs as early as 40 min and persists for at least 100 min; thereafter, resensitization becomes the dominant process.