RATIONALE: Mice lacking the dopamine transporter (DAT(-/-)) exhibit high extracellular dopamine levels and marked hyperactivity. This hyperlocomotion is paradoxically decreased by acute administration of amphetamine-like psychostimulants, an effect that has been previously related to the activation of serotonergic neurotransmission. OBJECTIVES: The goal of the present study was to investigate the effects of acute and daily administration of d-amphetamine on the locomotor activity of DAT(-/-) mice and examine the development of behavioral sensitization. In addition, we tested the implication of the serotonin system in the observed effects. METHODS: DAT(+/+), DAT(+/-), and DAT(-/-) mice were injected with acute amphetamine (0, 0.3, 1, 3, or 10 mg/kg, SC), repeated amphetamine (1 mg/kg for 8 days, SC), or with the serotonin reuptake inhibitor fluoxetine (0, 5, 10, or 20 mg/kg, SC) and their locomotor activity was evaluated. Moreover, the expression of the serotonin transporter and 5-HT(1A) receptors in the brain of DAT(-/-) mice was studied using autoradiography. RESULTS: Acute and repeated d-amphetamine injection (1 mg/kg) induced an hypolocomotor response in DAT(-/-) and DAT(+/-) mice, but only DAT(+/-) mice developed locomotor sensitization to the drug. Acute treatment with fluoxetine decreased locomotion in DAT(-/-) mice in a dose-dependent manner. The common hypolocomotor effect induced by d-amphetamine and fluoxetine in DAT(-/-) mice suggests an action on the serotonin transporter. However, autoradiography of the serotonin transporter and 5-HT(1A) receptors showed normal density and distribution in the brain, suggesting no compensatory effects due to the deletion of the DAT. CONCLUSIONS: These findings indicate that partial or total DAT gene deletion result in decreased locomotion in response to d-amphetamine and modify behavioral sensitization depending on the proportion of DAT removed, suggesting that inhibition of the DAT is necessary for the development of sensitization to psychostimulant drugs.