Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems.

The effects of 3,4-dihydroxymethamphetamine (DHM) and 2,4,5-trihydroxymethamphetamine (THM) on central serotonergic and dopaminergic systems were investigated to determine if these metabolites share the neurochemical properties of 3,4-methylenedioxymethamphetamine. THM (50-200 micrograms) or DHM (135 micrograms) was administered i.c.v. to rats; 5 days later, cortical, striatal and hippocampal tryptophan hydroxylase (TPH) activity were decreased by THM in a dose-dependent manner, whereas DHM was without effect in these brain structures. The concentration of serotonin in the brain structures contralateral to the side of THM injection was also decreased, but to a lesser degree. THM (100 and 200 micrograms) increased TPH activity to 155% of control in the dorsal raphe, whereas a dose of 50 micrograms increased TPH activity to 132% of control in the median raphe nucleus. THM also markedly reduced striatal tyrosine hydroxylase activity, but did not alter enzyme activity in the substantia nigra; DHM increased striatal tyrosine hydroxylase activity to 115% of control. These results suggest that THM, but not DHM, is toxic to both dopaminergic and serotonergic nerve terminals. Although THM could not be established as the neurotoxic metabolite explaining 3,4-methylenedioxymethamphetamine (MDMA) toxicity, its properties may prove useful in elucidating amphetamine toxicity.