In mice administered chronic stress--repeated overnight restraint stress for 7 days--there was a prolonged enhancement of dopamine (DA) uptake into synaptosomes. The mRNA for the DA transporter (DAT) was found to be concomitantly increased in the midbrain, as was the binding of the transporter ligand mazindol to DAT in the nucleus accumbens and caudate-putamen. Kinetic analysis showed an increase in Vmax for DA, with little change in Km. No changes in tyrosine hydroxylase activity and tissue DA or 3,4-dihydroxyphenylacetic acid (DOPAC) content were observed. However, homovanillic acid (HVA) was found to be increased in the striatum of the stressed animals. Enhanced DAT activity attributable to chronic stress was still observed in animals treated with the DA D2 receptor antagonist haloperidol or the glucocorticoid receptor antagonist mifepristone. Modulation of DAT activity may be a physiological mechanism for regulating the concentration of DA that reaches receptors, following periods of stress.