Assessment of the role of α-methylapinine in the neurotoxicity of MDMA

doi:10.1016/0091-3057(91)90289-E

Pharmacology Biochemistry and Behavior

Volume 38, Issue 2, February 1991, Pages 345-351

https://doi.org/10.1016/0091-3057(91)90289-E Get rights and content

Abstract

To assess the potential involvement of metabolism of 3,4-methylenedioxymethamphetamine (MDMA) to the catechol α-methylepinine in producing serotonergic neurotoxicity, we attempted to correlate aspects of this reaction with the neurotoxicity profile of MDMA. In contrast to the stereoselectivity of S-(+)-MDMA in causing persistent declines in rat brain 5-hydroxynidole levels, no stereochemical component to the metabolic reaction was apparent. Rat liver microsomes generated a significantly greater amount of α-methylepinine than did mouse microsomes, but similar amounts of metabolite were produced by brain microsomes from the two species. Formation of α-methylepinine by hepatic, but not brain, microsomes was inhibited by SKF 525A and induced by phenobarbital, possibly indicating a tissue specificity in cytochrome P-450-dependent metabolism of MDMA. To directly assess whether α-methylepinine is a likely mediator of MDMA neurotoxicity, the compound was administered intracerebroventricularly. No persistent declines in biogenic amines or their metabolites were observed one week following treatment. These data suggest that α-methylepinine alone is not responsible for the neurotoxic effects of MDMA.

References (43)

G. Battaglia et al.
MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons
Pharmacol. Biochem. Behav.
(1988)
M. Bradford
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
(1976)
J.F. Brady et al.
Spectral and inhibitory interactions of (±)-3,4-methylenedioxyamphetamine (MDA) and (±)-methylenedioxymethamphetamine (MDMA) with rat hepatic microsomes
Life Sci.
(1986)
U. Braun et al.
Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine)
J. Pharmacol. Sci.
(1980)
D.L. Commins et al.
Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine
Brain Res.
(1987)
R.L. Fitzgerald et al.
Stereochemistry of the metabolism of MDMA to MDA
Life Sci.
(1989)
R.W. Fuller et al.
Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine
Eur. J. Pharmacol.
(1975)
M.P. Johnson et al.
Effects of the enantiomers of MDA, MDMA and related analogues on [³H]-serotonin and [³H]-dopamine release from superfused rat brain slices
Eur. J. Pharmacol.
(1986)
B.J. Logan et al.
Differences between rats and mice in MDMA (methylenedioxymethamphetamine) neurotoxicity
Eur. J. Pharmacol.
(1988)
H.S. Maker et al.
Amine-mediated toxicity: The effects of dopamine, norepinephrine, 5-hydroxytryptamine, 6-hydroxydopamine, ascorbate, glutathione and peroxide on the in vivo activities of creatinine and adenylate kinases in the brain of the rat
Neuropharmacology
(1986)

G.M. Marquardt et al.

Metabolism of β-3,4-methylenedioxyamphetamine in the rat

Biochem. Pharmacol.

(1978)

G. Ricaurte et al.

Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study

Brain Res.

(1980)

C.J. Schmidt et al.

In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain

Biochem. Pharmacol.

(1987)

C.J. Schmidt et al.

Depression of rat brain tryptophan hydroxylase activity following the acute administration of methylenedioxymethamphetamine

Biochem. Pharmacol.

(1987)

C.J. Schmidt et al.

Direct central effects of acute methylenedioxymethamphetamine on serotonergic neurons

Eur. J. Pharmacol.

(1988)

L.S. Seiden et al.

Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine

Pharmacol. Biochem. Behav.

(1984)

T.D. Steele et al.

Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [³H]monoamines into synaptosomes from different regions of rat brain

Biochem. Pharmacol.

(1987)

T.D. Steele et al.

MDMA transiently alters biogenic amines and metabolites in mouse brain and heart

Pharmacol. Biochem. Behav.

(1989)

L.R. Steranka et al.

Long-term effects of continuous exposure to p-chloroamphetamine on central serotonergic mechanisms in mice

Biochem. Pharmacol.

(1978)

D.M. Stone et al.

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain

Eur. J. Pharmacol.

(1986)

D.M. Stone et al.

Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats

Neuropharmacology

(1987)

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Citation Excerpt :
This strain difference highlights the necessity and usefulness of mouse models to complement the results obtained with rats and primates to understand the mechanisms by which MDMA exerts its effects. The majority of past studies have used a pharmacological approach to study the biology (Hashimoto et al., 1993; Lim et al., 1992; 1993), neurotoxicity (Stone et al., 1987a; Battaglia et al., 1988; Hashimoto and Goromaru, 1990; Logan et al., 1988; Steele et al., 1989; 1991; Green et al., 1995; O'Shea et al., 2001; Colado et al., 2001), adverse physiological effects (Carvalho et al., 2001, 2002; Johnson et al., 2002a,b; Gesi et al., 2002a,b; Fantegrossi et al., 2003), behavioural effects (Glennon et al., 1987; Miczek and Haney, 1994; Dulawa and Geyer, 1996; Fantegrossi et al., 2003), addictive potential (Daza-Losada et al., 2007) and damaging effects of MDMA on cognition after repeated consumption of this drug (Camarasa et al., 2012; García-Pardo et al., 2017c). However, in the last few decades, several transgenic and knockout (KO) mouse models have been developed and have contributed greatly to our understanding of the neurobiological substrates of hyperlocomotion, reward, neurotoxicity and hyperthermia induced by MDMA (see review by Stove et al., 2010).
MDMA (3,4-methylendioxymethamphetamine), also known as Ecstasy, is a stimulant drug recreationally used by young adults usually in dance clubs and raves. Acute MDMA administration increases serotonin, dopamine and noradrenaline by reversing the action of the monoamine transporters. In this work, we review the studies carried out over the last 30 years on the neuropsychobiological effects of MDMA in humans and mice and summarise the current knowledge. The two species differ with respect to the neurochemical consequences of chronic MDMA, since it preferentially induces serotonergic dysfunction in humans and dopaminergic neurotoxicity in mice. However, MDMA alters brain structure and function and induces hormonal, psychomotor, neurocognitive, psychosocial and psychiatric outcomes in both species, as well as physically damaging and teratogen effects. Pharmacological and genetic studies in mice have increased our knowledge of the neurochemical substrate of the multiple effects of MDMA. Future work in this area may contribute to developing pharmacological treatments for MDMA-related disorders.
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy)-mediated production of hydrogen peroxide in an in vitro model: The role of dopamine, the serotonin-reuptake transporter, and monoamine oxidase-B
2004, Neuroscience Letters
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) has been shown to induce long-term deficits in serotonergic function in animal models. Several studies have suggested that dopamine (DA) uptake into serotonin (5-HT) terminals by the 5-HT reuptake transporter (SERT) and subsequent deamination by monoamine oxidase-B (MAO-B) leads to the formation of hydrogen peroxide and may be major contributors to this serotonergic toxicity. In the present study, when human choriocarcinoma (JAR) cells were exposed to MDMA (1.2 mM) for 6 h, followed by treatment with DA (0.1 mM), hydrogen peroxide production increased over a 24 h period, peaking at 420% over baseline and decreasing cell viability by 30%. DA alone increased hydrogen peroxide production 84% over baseline, but did not significantly decrease cell viability. Incubation of MDMA treated cells with the SERT inhibitor, fluoxetine (500 nM) or the MAO-B inhibitor, l-deprenyl (0.1 mM) for 30 min prior to DA, significantly blocked free radical production and cell death. These findings support the hypothesis that the deamination of DA by MAO-B within the serotonergic cell can lead to hydrogen peroxide formation and ultimately cell death.
Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion
1996, Biochemical Pharmacology
3,4-Methylenedioxymethamphetamine (MDMA) affects both dopamine and serotonin (5-HT) systems. One of its acute actions is to cause a reversible fall in steady-state brain 5-HT concentrations. To investigate the chemical basis of this acute effect, the brain levels of the parent compound and three major metabolites, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (DHMA) and 6-hydroxy-3,4-methylenedioxymethamphetamine (6-OHMDMA), were monitored, together with 5-HT levels, over a period of 6 hr in male Sprague-Dawley (SD) rats. The temporal relationships between drug concentrations of both stereoisomers and depletions were evaluated first. There was no correlation between the concentrations of the compounds measured and the extent of 5-HT depletion. Brain levels of MDMA and MDA were higher than plasma levels and exhibited a stereoselectivity in that (−)-MDMA and (+)-MDA levels were higher than those of their enantiomers. The relationship between the dose of (+)-MDMA and reduction in 5-HT levels was next investigated in SD male, SD female, and Dark Agouti (DA) female rats. These animals exhibit different capabilities of MDMA metabolism. There is a lower level of MDA, the N-demethylated metabolite of MDMA, in female SD rats than in males. Female DA rats are deficient in CYP2D isozymes, one of the enzymes responsible for demethylenation of MDMA to DHMA at pharmacological concentrations of substrate. There was a significant accumulation of MDMA in the brain and plasma of DA rats, but their 5-HT depletion was somewhat attenuated. The results indicated that MDMA was apparently not the single, causative agent for the acute 5-HT depletion, which may also involve a metabolite formed by CYP2D.
Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity
1993, Pharmacology, Biochemistry and Behavior
The effect of acute, reversible depletion of either serotonin [5-hydroxytryptamine (5-HT)] or dopamine (DA) on the long-term (7-day) decrease of brain 5-HT content produced after 3,4-methylenedioxymethamphetamine (MDMA) administration was investigated. The tyrosine hydroxylase inhibitor α-methyl-p-tyrosine (α-MPT) significantly attenuated the acute increase in DA efflux produced by MDMA in the striatum as measured by in vivo microdialysis. Treatment with α-MPT had no effect on MDMA-induced 5-HT release. α-MPT treatment blocked the long-term (7-day) depletion of striatal 5-HT content after MDMA administration. The tryptophan hydroxylase inhibitor p-chlrophenylalanin (PCPA) completely blocked the acute increase in the extracellular concentration of 5-HT produced by MDMA. Although PCPA significantly attenuated the increase in DA efflux produced by MDMA, the effect was small in magnitude. More importantly, treatment with PCPA had no effect on MDMA-induced decrease of 5-HT uptake sites in the frontal cortex. These data are suggestive that acute depletion of DA but not 5-HT protects againts the long-term neurotoxic effects of MDMA on 5-HT axon terminals. In addition, these data are supportive of the hypothesis that DA plays a major role in the neurotoxic effects of MDMA.
Long-term alteration in the central monoaminergic systems of the rat by 2,4,5-trihydroxyamphetamine but not by 2-hydroxy-4,5-methylenedioxymethamphetamine or2-hydroxy-4,5-methylenedioxyamphetamine
1992, European Journal of Pharmacology
The long-term effects of three metabolites of 3,4-methylenedioxymethamphetamine (MDMA) on the central monoaminergic systems of the rat were examined. Seven days after the intracerebroventricular administration of 0.25 and 0.5 μmol 2,4,5-trihydroxyamphetamine, hippocampal tryptophan hydroxylase (TPH) activity was reduced to 5 and 1% of control, respectively, while norepinephrine (NE) concentration was depressed to 10 and 18% of control. These two respective dosages also decreased striatal tyrosine hydroxylase (TH) activity to 67 and 10% of control, respectively, while nigral TH activity was reduced to 59 and 20% of control. Striatal TPH activity was reduced to 74 and 81% of control, respectively, while the activity in the dorsal and median raphe remained unaltered. The intracerebroventricular administration of 1 μmol 2-hydroxy-4,5-methylenedioxymethamphetamine (6-OH-MDMA) failed to alter TPH activity, TH activity or NE concentration after 14 days. In contrast, 1 μmol of 2-hydroxy-4,5-methylenedioxyamphetamine (6-OH-MDA) induced a 30% increase in striatal TPH activity and a 50% increase in nigral TH activity. The study of the formation of 2,4,5-trihydroxyamphetamine after MDMA treatment may provide insight as to how MDMA destroys serotonergic nerve terminals.
Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate
2011, Chemical Research in Toxicology

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¹: Present address: Department of Physiology, School of Medicine, University of Maryland at Baltimore, 655 West Baltimore Street, Baltimore, MD 21201.

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Assessment of the role of α-methylapinine in the neurotoxicity of MDMA

Abstract

Pharmacol. Biochem. Behav.

Anal. Biochem.

Life Sci.

J. Pharmacol. Sci.

Brain Res.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Biochem. Pharmacol.

Brain Res.

Biochem. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Biochem. Pharmacol.

Pharmacol. Biochem. Behav.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology