||The effects of multiple toxic doses of methamphetamine on catecholaminergic, serotonergic, and cholinergic metabolism in the neostriatum, nucleus accumbens, olfactory tubercle, and median eminence area of the rat brain have been investigated. Methamphetamine (15 mg/kg, s.c.) was administered every 6 hours for 5 doses. Thirty-six hours after the first of 5 doses, tyrosine hydroxylase (TH) activity as well as dopamine and norepinephrine levels were significantly decreased in the neostriatum and olfactory tubercle but were not altered in the nucleus accumbens or median eminence area. Prior to the 36-hour time point, drug treatment did significantly decrease TH activity in the neostriatum (at 3, 12, and 24 hours) and olfactory tubercle (at 24 hours) but did not change the enzyme activity in the nucleus accumbens. At 0.5, 7, 15 and 30 days after 5 doses of methamphetamine, TH activity in the neostriatum was significantly decreased by at least 38%. In the olfactory tubercle, TH activity was also significantly decreased at 0.5, 15, and 30 days but was not decreased at 7 days after the last dose. Only a slight change in TH activity occurred in the nucleus accumbens at 15 and 30 days after drug treatment. In contrast, tryptophan hydroxylase (TPH) activity was significantly decreased in the neostriatum, nucleus accumbens, and olfactory tubercle by 75% 3 hours after the first dose. TPH activity remained depressed, by at least 65%, at 30 days after the fifth dose in all 3 areas. Methamphetamine caused a slight decrease in choline acetyltransferase activity in olfactory tubercle at the 36-hour time point; however, it did not affect cholinergic enzyme activity in the neostriatum or nucleus accumbens. This evidence suggests that the serotonergic neurons are more sensitive to the toxic effects of methamphetamine than the dopaminergic neurons, whereas the cholinergic neurons seem to be unaffected.