It has been demonstrated that methamphetamine (METH) administration affects Na(+)/Cl(-)-dependent transporters; for example, METH treatment rapidly and reversibly decreases dopamine (DA) and serotonin (5HT) transporter function in rat striatum in vivo, as assessed in synaptosomes prepared from METH-treated rats. Because acute effects of METH on other transporters within this family have been less studied, the responses of norepinephrine (NE) and gamma-aminobutyric acid (GABA) transporters to METH administration(s) were determined. Both single and multiple METH administrations inhibited hippocampal NE uptake 1 h after METH treatment(s). In contrast, striatal GABA uptake was not affected by either treatment paradigm. The effects observed after both single and multiple METH administrations on NE transporters were attributable to increases in K(m,) with no changes in V(max); effects that were eliminated by repeated washing of the synaptosomes. These 'washout' data suggest that residual METH introduced by the in vivo subcutaneous injection(s) directly reduced NE transporter activity in the in vitro assay and that, unlike DA and 5HT transporters, METH did not indirectly alter NE transporter function. Taken together, these data demonstrate differences in the responses of NE, GABA, DA, and 5HT transporters to METH treatment.