In this experiment, we examined the modulatory effects of testosterone on the parkinsonism-inducing drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in two strains of mice. Orchidectomized male CD-1 and C57/B1 mice were implanted with either empty Silastic capsules or capsules containing testosterone and subsequently treated with MPTP. A small area of the corpus striatum was removed for determination of dopamine (DA) content, whereas the remainder was superfused and used to measure L-DOPA (5 microM)-evoked DA release. In animals treated with MPTP, L-DOPA-evoked DA release was reduced significantly in CD-1 mice, but not in C57/B1 mice, treated with testosterone. No differences in L-DOPA-stimulated DA release between MPTP-versus vehicle-treated mice was observed in either the CD-1 or C57/B1 mice receiving empty Silastic capsules. Corpus striatum DA contents were more severely depleted in the MPTP-sensitive C57/B1 versus the CD-1 mouse strain irrespective of hormone treatment. These results confirm previous results demonstrating differences in these two mouse strains in response to the neurotoxic effects of MPTP upon corpus striatum DA content. More interestingly, they show an important differential modulatory effect of testosterone upon L-DOPA-evoked DA release as a function of MPTP treatment and indicate that testosterone significantly alters the neurotoxic effects of MPTP in the CD-1 mouse.