Tolerance to the neurotoxic effect of methamphetamine in rats behaviorally sensitized to methamphetamine or amphetamine

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. (C) 1997 Elsevier Science B.V.