ROLE OF METHAMPHETAMINE METABOLISM IN THE DEVELOPMENT OF CNS TOLERANCE TO THE DRUG

We have previously observed that pretreatment with increasing doses of methamphetamine (METH) attenuates the effects of METH on the dopaminergic and serotonergic systems as compared with the ones observed in nonpretreated controls. In order to understand the mechanism of this tolerance, untreated rats (naive) and rats pretreated with METH (daily doses of 2.5, 5.0, 7.5, and 10 mg/kg, s.c., at 6h intervals with a 24h drug-free period between each dose) were challenged with the administration of 5 doses of METH (15 mg/kg, s.c., at 6h intervals). The metabolism of METH in brain, liver, and blood was studied by measuring the concentration of METH and its metabolites 2, 4, 6, 8 and 10h after the last dose by gas chromatography/mass spectrometry techniques.