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.
Abekawa
T
T
Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.
Ohmori
T
T
Koyama
T
T
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D008694:Methamphetamine / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
D015306:Biogenic Monoamines; D015259:Dopamine Agents; D009498:Neurotoxins; D012701:Serotonin; D008694:Methamphetamine; D000661:Amphetamine