Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity

The psychotropic amphetamine derivatives 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) have been used for recreational and therapeutic purposes in man. In rats, these drugs cause large reductions in brain levels of serotonin (5-HT). This study employs immunocytochemistry to characterize the neurotoxic effects of these compounds upon monoaminergic neurons in the rat brain. Two weeks after systemic administration of MDA or MDMA (20 mg/kg, s.c., twice daily for 4 d), there is profound loss of serotonergic (5-HT) axons throughout the forebrain; catecholamine axons are completely spared. Regional differences in drug toxicity are exemplified by partial sparing of 5-HT axons in hippocampus, lateral hypothalamus, basal forebrain, and in some areas of neocortex. The terminals of 5-HT axons are selectively ablated, while axons of passage and raphe cell bodies are spared. Thickened preterminal fibers exhibit increased staining due to damming-up of neurotransmitter and other axonal constituents. Fine 5- HT axon terminals are extremely vulnerable to these drugs, whereas terminal-like axons with large varicosities survive, raising the possibility that some 5-HT axons may be resistant to the neurotoxic effects. At short survivals, visualization of greatly swollen, fragmented 5-HT axons provides anatomic evidence for degeneration of 5- HT projections. The results establish that MDA and MDMA produce structural damage to 5-HT axon terminals followed by lasting denervation of the forebrain. Both drugs have similar effects, but MDA produces a greater reduction of 5-HT axons than does MDMA at the same dosage. The selective degeneration of 5-HT axons indicates that these drugs may serve as experimental tools to analyze the organization and function of 5-HT projections. Caution should be exercised until further studies determine whether these compounds may be hazardous in man.

• Publication year

  1988

• Venue

  Journal of Neuroscience

• Publication date

  1988-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.08-08-02788.1988PMID 2457659PMCID PMC6569396
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Distinct morphologic classes of serotonergic axons in primates exhibit differential vulnerability to the psychotropic drug 3,4-methylenedioxymethamphetamine.

  1989cited by this paper
• Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA).

  1988cited by this paper
• (+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates.

  1988cited by this paper
• MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons.

  1988cited by this paper
• Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.

  1987cited by this paper
• 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites.

  1987cited by this paper
• The serotoninergic innervation of cerebral cortex: Different classes of axon terminals arise from dorsal and median raphe nuclei

  1987cited by this paper
• Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

  1987cited by this paper
• The psychological and physiological effects of MDMA on normal volunteers.

  1986cited by this paper
• Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue.

  1986cited by this paper
• The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain.

  1986cited by this paper
• Subjective reports of the effects of MDMA in a clinical setting.

  1986influential reference
• Can drugs be used to enhance the psychotherapeutic process?

  1986cited by this paper
• Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens.

  1986cited by this paper
• MDMA. Nonmedical use and intoxication.

  1986cited by this paper
• The neostriatal mosaic. I. compartmental organization of projections from the striatum to the substantia nigra in the rat

  1985cited by this paper
• Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals.

  1985influential reference
• MDA: an agent that produces stimulus effects similar to those of 3,4-DMA, LSD and cocaine.

  1984cited by this paper
• Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: evidence from single unit studies in freely moving cats.

  1984cited by this paper
• Further investigation of the discriminative stimulus properties of MDA.

  1984cited by this paper
• 5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA).

  1984cited by this paper
• Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents.

  1984cited by this paper
• MDA: a psychoactive agent with dual stimulus effects.

  1984cited by this paper
• SELECTIVE (+)‐AMPHETAMINE NEUROTOXICITY ON STRIATAL DOPAMINE NERVE TERMINALS IN THE MOUSE

  1982cited by this paper
• Effects of certain hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain synaptosomes.

  1982cited by this paper
• Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain.

  1982cited by this paper
• Discriminative stimulus properties of MDA analogs.

  1982cited by this paper
• Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.

  1981cited by this paper
• Psychotherapy with psychedelic drugs: a case report.

  1981cited by this paper
• Enhancement of the behavioral effects of 2,5-dimethoxy-4-methyl-amphetamine (DOM) by pretreatment with p-chlorophenylalanine.

  1980cited by this paper
• The serotonin innervation of the cerebral cortex in the rat--an immunohistochemical analysis.

  1980cited by this paper
• [Research on the central activity and analgesia of N-substituted analogs of the amphetamine derivative 3,4-methylenedioxyphenylisopropylamine].

  1980cited by this paper
• Mechanisms of regrowth in the bulbospinal serotonin system following 5,6-dihydroxytryptamine induced axotomy. II. Fluorescence histochemical observations.

  1980cited by this paper
• Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs.

  1979cited by this paper
• Localization of serotonin in the central nervous system by immunohistochemistry: description of a specific and sensitive technique and some applications.

  1978cited by this paper
• Absolute configuration and psychotomimetic activity.

  1978cited by this paper
• CHARACTERIZATION OF THREE NEW PSYCHOTOMIMETICS

  1978cited by this paper
• Psychotomimetic Drugs: Structure-Activity Relationships

  1978cited by this paper
• A pharmacologic comparison of 3,4-methylenedioxyamphetamine and LSD in the chronic spinal dog.

  1977cited by this paper
• The metabolism of amphetamines in mammals.

  1976cited by this paper
• Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys.

  1976cited by this paper
• MDA‐ASSISTED PSYCHOTHERAPY WITH NEUROTIC OUTPATIENTS: A PILOT STUDY

  1976cited by this paper
• Comparison of cardiovascular, hyperthermic, and toxic effects of para-methoxyamphetamine (PMA) and 3, 4-methylenedioxyamphetamine (MDA).

  1975cited by this paper
• Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine.

  1975cited by this paper
• Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms.

  1975cited by this paper
• Pharmacological actions of 6-hydroxydopamine.

  1974cited by this paper
• The use of neurotoxic dihydroxytryptamines as tools for morphological studies and localized lesioning of central indolamine neurons

  1973cited by this paper
• Evaluation of the effects of 5,7-dihydroxytryptamine on serotonin and catecholamine neurons in the rat CNS.

  1973cited by this paper
• The properties of 3,4-methylenedioxyamphetamine (MDA). I. A review of the literature.

  1973cited by this paper
• Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain.

  1972cited by this paper
• Action of psychotogenic drugs on single midbrain raphe neurons.

  1970cited by this paper
• Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe

  1968cited by this paper
• Monoamine levels and neuronal degeneration in rat brain following lateral hypothalamic lesions.

  1967cited by this paper
• Monoamine levels and neuronal degeneration in rat brain following lateral hypothalamic lesions.

  1967cited by this paper
• Evaluation of 3,4-methylenedioxyamphetamine (MDA) as an adjunct to psychotherapy.

  1967cited by this paper
• Effects of LSD-25 on brain serotonin.

  1961cited by this paper
• Pharmacological Effects

  year unknowncited by this paper
• The effects

  year unknowncited by this paper

• MDMA in Psychiatry: From PTSD to emerging indications, safety, and future directions

  2025cites this paper
• Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants

  2025cites this paper
• Effects of the designer drug 4-methylamphetamine on core temperature and serotonin levels in the striatum and hippocampus of rats.

  2024cites this paper
• Functional Regrowth of Norepinephrine Axons in the Adult Mouse Brain Following Injury

  2024cites this paper
• A review of the effects of pharmaceutical pollutants on humans and aquatic ecosystem

  2024cites this paper
• Chronic Treatment with Serotonin Selective Reuptake Inhibitors Does Not Affect Regrowth of Serotonin Axons Following Amphetamine Injury in the Mouse Forebrain

  2024influential citation
• Psychedelic Therapy: A Primer for Primary Care Clinicians—3,4-Methylenedioxy-methamphetamine (MDMA)

  2024cites this paper
• Role of Serotonergic System in Regulating Brain Tumor-Associated Neuroinflammatory Responses.

  2024cites this paper
• Serotonin 2C receptors are also important in head-twitch responses in male mice

  2023cites this paper
• Cerebrospinal Fluid Serotonin level as Biomarker for Neurotoxicity after 3,4-Methylenedioxymethamphetamine (MDMA)

  2022cites this paper
• Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines.

  2022cites this paper
• Neuronal Redevelopment and the Regeneration of Neuromodulatory Axons in the Adult Mammalian Central Nervous System

  2022cites this paper
• White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels

  2022cites this paper
• Preliminary Results on the Long-Term Effects of Dextromethorphan on MDMA-Mediated Serotonergic Deficiency and Volumetric Changes in Primates Based on 4-[18F]-ADAM PET/MRI

  2022cites this paper
• A Systematic Review of the MDMA Model to Address Social Impairment in Autism

  2021cites this paper
• Neurotoxicity in Psychostimulant and Opiate Addiction

  2021cites this paper
• Pharmacology of Drugs Used as Stimulants

  2021cites this paper
• Exercise Regulates Peripheral Blood Serotonin to Improve the Addiction and Impulse of Methamphetamine Withdrawal Patients

  2021cites this paper
• Ecstasy : la deuxième vague…

  2021cites this paper
• Cognitive consequences of 3,4-methylenedioxymethamphetamine use

  2020cites this paper
• Comprehensive Topographical Map of the Serotonergic Fibers in the Mouse Brain

  2020cites this paper
• Comprehensive topographical map of the serotonergic fibers in the male mouse brain

  2020cites this paper
• An investigation into the antidyskinetic and reinforcing effects of UWA-101 in Sprague Dawley rats

  2020cites this paper
• Autophagy inhibition plays a protective role against 3, 4‐methylenedioxymethamphetamine (MDMA)‐induced loss of serotonin transporters and depressive‐like behaviors in rats

  2019cites this paper
• Catecholaminergic axons in the neocortex of adult mice regrow following brain injury

  2019influential citation
• Minocycline attenuates 3,4-methylenedioxymethamphetamine-induced hyperthermia in the rat brain.

  2019cites this paper
• Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine.

  2018cites this paper
• Serotonin axons in the neocortex of the adult female mouse regrow after traumatic brain injury

  2018influential citation
• Decision‐making in chronic ecstasy users: a systematic review

  2017cites this paper
• In vitro cellular models for neurotoxicity studies : neurons derived from P19 cells

  2017cites this paper
• Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise.

  2017cites this paper
• Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine

  2017cites this paper
• Degeneration of serotonin neurons triggers spasticity in amyotrophic lateral sclerosis

  2017cites this paper
• Receptor visualization and the atomic bomb. A historical account of the development of the chemical neuroanatomy of receptors for neurotransmitters and drugs during the Cold War.

  2017cites this paper
• The effects of ecstasy on neurotransmitter systems: a review on the findings of molecular imaging studies

  2016cites this paper
• Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells

  2016cites this paper
• The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

  2016cites this paper
• Clinical applications of hallucinogens: A review.

  2016cites this paper
• Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury.

  2016cites this paper
• The effect of MDMA self-administration on MDMA-produced hyperactivity and c-fos expression

  2016cites this paper
• Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

  2015cites this paper
• 3,4-methylenedioxy-methamphetamine(MDMA)-induced increases in hippocampal glutamate concentrations and its impact on the dentate gyrus

  2015cites this paper
• The neurotoxicity of amphetamines during the adolescent period

  2015cites this paper
• Ondansetron attenuates co-morbid depression and anxiety associated with obesity by inhibiting the biochemical alterations and improving serotonergic neurotransmission.

  2015cites this paper
• MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

  2015cites this paper
• Monoamine Reuptake Inhibitors in Parkinson's Disease

  2015cites this paper
• Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study

  2015influential citation
• Neuropharmacology and toxicology of novel amphetamine-type stimulants

  2015cites this paper
• Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine.

  2014cites this paper
• Catechol-o-methyltransferase and 3,4-({+/-})-methylenedioxymethamphetamine toxicity.

  2014cites this paper
• Axonal Targeting of the Serotonin Transporter in Cultured Rat Dorsal Raphe Neurons Is Specified by SEC24C-Dependent Export from the Endoplasmic Reticulum

  2014cites this paper
• Treadmill exercise exerts an antidepressant-like effect to mice submitted to a neurotoxic methamphetamine dose

  2014cites this paper
• Serotonin reuptake transporter deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in SERT-KO rats.

  2014cites this paper
• Effects of MDMA on the Human Nervous System

  2014cites this paper
• The Role of Serotonin in MDMA Self-administration in Rats

  2014cites this paper
• Age differences in (±) 3,4-methylenedioxymethamphetamine (MDMA)-induced conditioned taste aversions and monoaminergic levels.

  2014cites this paper
• Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its metabolites.

  2014cites this paper
• Brain and Peripheral Organ Toxicity of "Ecstasy" in Adolescent Rats in Human Relevant Doses

  2014cites this paper
• Male and female ecstasy users: differences in patterns of use, sleep quality and mental health outcomes.

  2013cites this paper
• Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

  2013cites this paper
• Modulation of 3,4-methylenedioxymethamphetamine effects by endocannabinoid system.

  2013cites this paper
• Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

  2013cites this paper
• Ecstasy¿s Neurotoxicity: In Vitro Findings from Mitochondria to the Cell

  2013influential citation
• Challenging the Serotonin System: A Mechanistic Approach to the Method of Acute Tryptophan Depletion in Rodents

  2013cites this paper
• Methylenedioxymethamphetamine-induced neurotoxicity: The role of hepatic enzymes cytochrome p450 2d6 and catechol-o-methyltransferase and contribution of microglia

  2013cites this paper
• Effects of a short-course MDMA binge on dopamine transporter binding and on levels of dopamine and its metabolites in adult male rats.

  2013cites this paper
• Toxicity of amphetamines: an update

  2012cites this paper
• Brain Imaging in Behavioral Neuroscience

  2012cites this paper
• Methylenedioxymethamphetamine (Ecstasy, MDMA)

  2012cites this paper
• Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain

  2012cites this paper
• The Regulation of Brain Serotonergic and Dopaminergic Neurons: The Modulatory Effects of Selective Serotonin Reuptake Inhibitors, Atypical Neuroleptics and Environmental Enrichment

  2012cites this paper
• Behavioural and Neurochemical Consequences of MDMA Self-Administration in Rats

  2012cites this paper
• (±)3,4‐methylenedioxymethamphetamine (“ecstasy”) treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain

  2012cites this paper
• Chapter 11 – Raphe Nuclei

  2012cites this paper
• Studies of (±) 3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

  2012cites this paper
• Projections and interconnections of genetically defined serotonin neurons in mice

  2012cites this paper
• Toxicity of amphetamines: an update Marcia CarvalhoHelena CarmoVera Marisa CostaJoao Paulo Capela • Helena PontesFernando RemiaoFelix CarvalhoMaria de Lourdes Bastos

  2012cites this paper
• Repeated exposure to MDMA and amphetamine: sensitization, cross-sensitization, and response to dopamine D1- and D2-like agonists

  2012cites this paper
• Structural, functional and spectroscopic MRI studies of methamphetamine addiction.

  2012cites this paper
• Altered serotonergic neurotransmission as a main player in the pathophysiology of Alzheimer's disease : structural and ultrastructural studies in a triple transgenic mouse model of the disease

  2012cites this paper
• The serotonergic system in ageing and Alzheimer's disease.

  2012cites this paper
• An Investigation of CYP2B in Rat Brain: Regulation and Role in Drug and Toxin Response

  2012cites this paper
• Glutamate and MDMA Neurobehavioral Toxicity

  2012cites this paper
• Pro‐oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

  2012cites this paper
• Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’): Neurodegeneration versus Neuromodulation

  2011cites this paper
• Rats preexposed to MDMA display attenuated responses to its aversive effects in the absence of persistent monoamine depletions

  2011cites this paper
• In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users.

  2011cites this paper
• Caractérisations biochimique anatomique et comportementale des souris dépourvues de la protéines STOP : un modèle expérimental pour l'étude de symptômes psycho-affectifs

  2011cites this paper
• Neuroadaptive Changes in  5-HT1A Autoreceptor Sensitivity  Following High-Dose MDMA Treatment

  2011cites this paper
• Evaluation of Bcl-2 Family Gene Expression in Hippocampus of 3, 4-methylenedioxymethamphetamine Treated Rats

  2011cites this paper
• Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat

  2011influential citation
• Altered pain responses in abstinent (±)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) users

  2011cites this paper
• The Nature of 3, 4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis

  2011cites this paper
• Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) Enantiomers In Vitro and in the MPTP-Lesioned Primate: R-MDMA Reduces Severity of Dyskinesia, Whereas S-MDMA Extends Duration of ON-Time

  2011cites this paper
• Enhanced hippocampal long-term potentiation following repeated MDMA treatment in Dark-Agouti rats.

  2011cites this paper
• A medicinal chemistry investigation of 3,4-Methylenedioxymethamphetamine (MDMA)

  2011cites this paper
• Effect of 3,4-methylenedioxyamphetamine on dendritic spine dynamics in rat neocortical neurons--involvement of heat shock protein 27.

  2011cites this paper
• Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA): regulation by CB2 receptors and implications for neurotoxicity

  2011cites this paper
• Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

  2011cites this paper
• MDMA toxicity and pathological consequences: a review about experimental data and autopsy findings.

  2010cites this paper