The present study examined whether the development in rats of behavioral sensitization to methamphetamine (MAP) is related to the development of neurotoxic morphological changes presumably induced in the medial prefrontal cortex (MFC). Male rats were intraperitonieally injected with MAP (5 mg/kg) once a day for 12 days (day 1-day 12), and then the drug was withdrawn for 7-42 days (WD7-WD42). The MAP- treatment caused hypersensitivity of a successive head-movement stereotypy, which reached a basic plateau level on day 4, and rose successively to a higher level by day 12. Morphological changes were histochemically and morphometrically examined in the MFC. In the strata covering layers II and III, the densities of tyrosine hydroxylase (TH)-immunoreactive axons decreased on a daily basis to 50% of the control on day 4 and then to 40% on days 6 and 12. The densities of dopamine-,beta-hydroxylase (DBH)-immunoreactive axons did not change during the injection period. A few TUNEL-positive cells were observed in a unit area (0.25 mm2) covering layers II-V on day 6 and they increased to 19 and 16 on day 12 and WD7, respectively. These observations demonstrate a role for the neurotoxic changes in the MFC in the processes of behavioral sensitization of a stereotypy to a low dose of MAP.