A series of experiments was conducted to examine whether rats behaviorally sensitized to methamphetamine (MA) would show supersensitivity or tolerance to the MA-induced neurotoxic effects on dopaminergic and serotonergic nerve terminals in the striatum (ST), nucleus accumbens (NA) and medial frontal cortex (MFC). Moderate to high doses of MA (3, 4 and 5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) dose-relatedly decreased the contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in ST, and the content of 5-HIAA in NA and that of 5-HT in MFC. These neurotoxic effects in ST were significantly attenuated in rats behaviorally sensitized to MA (4 mg HCl salt/kg, s.c., for 10 days). To examine the possibility that the attenuation in the toxic effects in sensitized rats was due to an accelerated metabolism from MA to amphetamine (AMPH), a high dose of MA (5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) was administered to rats behaviorally sensitized to AMPH (4 mg HCl salt/kg, s.c., for 10 days). It was revealed that the MA-induced decrease in the striatal contents of DOPAC, homovanillic acid (HVA), 5-HT and 5-HIAA were attenuated in rats behaviorally sensitized to AMPH. The MA-induced decrease in the striatal DA content tended to be attenuated in AMPH-sensitized rats. These data suggest that rats behaviorally sensitized to MA or AMPH develop tolerance to MA-induced striatal dopaminergic and serotonergic neurotoxicity. It is speculated that the mechanism of tolerance might be mediated by an altered central response rather than peripheral metabolism.