Beagle dogs pressed a lever under a 15-response fixed-ratio schedule of i.v. nicotine or cocaine infusion or water presentation. A 4-min time-out period followed each fixed-ratio trial and each daily session ended after 16 successive fixed-ratio trials. Both nicotine and cocaine were self-administered above saline levels, with the maximum number of infusions occurring at a dose of 30 micrograms/kg of nicotine and 100 micrograms/kg of cocaine. Rates of responding first increased, reaching a maximum at 10 to 30 micrograms/kg/infusion and then decreased, as the dose of nicotine or cocaine was varied between 3 and 300 micrograms/kg/infusion. The rate of responding and number of infusions obtained per session were higher under the schedule of cocaine self-administration than under the schedule of nicotine self-administration. Presession treatment with the nicotinic antagonist, mecamylamine (1.0 mg/kg i.v.), for seven consecutive sessions, decreased nicotine-maintained responding to levels not unlike those seen when saline was substituted for drug. Neither cocaine- nor water-maintained responding was affected by presession treatment with mecamylamine. A second group of beagle dogs pressed a lever under a schedule of i.v. nicotine (50-400 micrograms/kg/infusion) or cocaine (200-1600 micrograms/kg/infusion) infusion in which the fixed-ratio requirement was increased daily (i.e., a progressive-ratio schedule). The maximum fixed-ratio value at which responding was maintained first increased as the dose per infusion increased and then, at the highest dose, either remained the same or decreased. Cocaine maintained considerably higher fixed-ratio values than did nicotine, but maximum fixed-ratio values for nicotine were well above those seen with saline. The effects of i.v. nicotine (3, 30 or 300 micrograms/kg) or mecamylamine (1.0 mg/kg) on heart rate, rectal temperature and pupillary diameter were measured in a third group of beagle dogs. Nicotine produced dose- and time-related changes in all three physiological parameters; the effects of mecamylamine were considerably greater than those seen with nicotine.