Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems.
Michel Johnson, I. Elayan, Glen R. Hanson, R. L. Foltz, James W. Gibb, H. Lim
Journal of Pharmacology and Experimental Therapeutics May 1, 1992 DOI: 10.1016/s0022-3565(25)11059-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | 3 4-dihydroxymethamphetamine (DHM) 2 4 5-trihydroxymethamphetamine (THM) |
| Dose | THM 50-200 micrograms; DHM 135 micrograms |
| Duration | 5 days after injection |
| Measures | tryptophan hydroxylase (TPH) activity, serotonin concentration, tyrosine hydroxylase activity |
| Topics | MDMA Serotonin |
| Key findings | THM, but not DHM, appears toxic to both dopaminergic and serotonergic nerve terminals: it dose-dependently reduced cortical, striatal, and hippocampal tryptophan hydroxylase activity and serotonin levels and markedly lowered striatal tyrosine hydroxylase activity, while DHM increased striatal tyrosine hydroxylase activity to 115% of control. The authors state THM could not be established as the neurotoxic metabolite explaining MDMA toxicity. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 21
- 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans Addiction May 1, 1994
- The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype British Journal of Pharmacology August 1, 1995
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration British Journal of Pharmacology February 1, 1999
- Fatal multi-organ failure after suicidal overdose with MDMA, `Ecstasy': case report and review of the literature Human & Experimental Toxicology February 1, 1999
and 16 more in the library