Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. The tumor suppressor gene, p53, is thought to play an important role in cell death. In the present study, we have assessed the participation of p53 in METH-induced serotonergic neurotoxicity, by using the mice lacking the gene for p53 protein. Three dosages (2.5, 5.0 and 10.0 mg/kg x 4) of METH were administered to wild-type (p53+/+), heterozygous (p53+/-) and homozygous (p53-/-) p53-knockout mice. The two lower doses caused no significant changes in serotonin (5-HT) transporters in any of the groups. The highest dose (10.0 mg/kg) caused significant decreases in striatal 5-HT transporters in wild-type (-31%) and heterozygous (-18%) mice. In contrast, 5-HT transporters were not significantly decreased in homozygous mice. These results suggest that the tumor suppressor, p53, plays an important role in METH-induced serotonergic neurotoxicity in mice brain. These data provide further evidence for a role of p53 in the neurotoxic effects of METH.