Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse.

4-Methylaminorex is an amphetamine analog which has recently gained attention due to its potential as a stimulant of abuse and the ease with which it is synthesized. Administration of acute and multiple doses of 4-methylaminorex caused rapid (3-h) and long-term (7-day) declines in striatal tryptophan hydroxylase activity with few changes in other serotonergic parameters. The acute response by tryptophan hydroxylase to this drug was reversed by incubating the tissues in a reducing environment suggesting that 4-methylaminorex alters this enzyme through oxidative mechanisms. The 4-methylaminorex-induced long-term reduction in tryptophan hydroxylase activity might be due to neurotoxic action on serotonergic systems. In contrast, although a decline in striatal tyrosine hydroxylase occurred 3 h following a single dose of 4-methylaminorex, no changes in this enzyme were observed at 7 days after acute or multiple dosing with this drug. This result suggests that 4-methylaminorex is not neurotoxic to the dopaminergic neurons. Even though this amphetamine analog apparently does not have long-term effects on dopaminergic systems, it does appear to enhance substantially dopaminergic activity. Evidence for increased dopamine activity resulting from 4-methylaminorex administration included dramatic but temporary rises in the levels of nigral neurotensin, dynorphin A and substance P following multiple drug administration. Similar peptide changes have been observed with other amphetamine-related stimulants and are mediated by increases in dopaminergic activity. In summary, 4-methylaminorex has significant impact on monoaminergic pathways. In general, its spectrum of effects on these systems is like that of the ring-substituted amphetamines, such as methylenedioxymethamphetamine.