Abstract The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH ‘challenge.’ In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH ‘runs’ common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.