Time-course of methamphetamine-induced neurotoxicity in rat caudate-putamen after single-dose treatment

The One-course of monoamine and tyrosine hydroxylase depletion after single -dose administration of D-methamphetamine (40 mg/kg s.c.) was investigated in caudate-putamen of male Sprague-Dawley rats. Times evaluated were 6, 12, 48, 72 and 240 h following treatment. Tyrosine hydroxylase was significant ly reduced by 29, 60, 66, 76 and 76% of central at each of the respective p ost-treatment time intervals. Dopamine was not reduced 6 h following treatm ent. Dopamine was significantly reduced by 53, 57, 68 and 74% 12, 48, 72 an d 240 h post-treatment, respectively. Reductions in caudate-putamen seroton in began earlier and wear ultimately larger than for dopamine, with signifi cant reductions of 28, 33 55, 74 and 81% at each of the respective post-tre atment intervals. Confirmation of neurotoxicity was provided by measurement of glial fibrillary acidic protein (GFAP) 240 h post-treatment. GFAP was i ncreased at this time interval by 150% above control. Methamphetamine-induc ed hyperthermia during the 6 h immediately after treatment was comparable a mong the groups of animals used for analyses at each time interval. The res ults demonstrate that methamphetamine-induced monoamine reductions in the c audate-putamen occur rapidly, peak at 75-80% below controls, and Last for a t least 10 days after a single dose. These effects are as large or larger t han those reported after the commonly used 10 mg/kgx4 dose treatment regime n administered at 2-h intervals and provides an alternate model for the inv estigation of methamphetnmine-induced neurstoxicity. (C) 2000 Elsevier Scie nce B.V. All rights reserved.