Rats were implanted with chronic intravenous cannulae and trained to bar press for intravenous, self-administered S(+)-amphetamine (AMPH). After establishment of a steady baseline at 0.25 mg/kg/reinforcement, the animals were removed from the test situation and subsequently injected three times a day four days with increasing amounts of AMPH (total=78 mg/kg). Thirty-six hours after the last injection, the animals were tested for tolerance to self-administered AMPH, and all the animals increased the amount of drug intake by at least 45% over baseline. The brain disppearance of a 10 mg/kg IV dose of AMPH was measured for the chronic AMPH and saline treated subjects to test for the possibility of enzyme induction. No differences were found. These data indicate that drug self-administration in rats is a useful paradigm to study tolerance to the rewarding effects of AMPH and indicate that drug self-administration in rats is a useful paradigm to study tolerance to the rewarding effects of AMPH and may be useful in understanding the mechanisms mediating the mood elevating properties of the drug observed in humans.