(±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals

Ricaurte, George A.; Yuan, Jie; McCann, Una D.

doi:10.1159/000026664

Cited by 277 publications

(204 citation statements)

References 35 publications

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“…246 These acute effects are followed by a temporary attenuation of central 5-HT. 247 There is evidence to indicate that MDMA has neurotoxic effects on the 5-HTergic system in animals 248 and humans, 249,250 mainly characterized by a decreased number of serotonin transporters. 249,251 Animal studies have indicated that MDMA administration results in long-term attenuation of brain 5-HT and 5-HIAA as well as attenuated TPH activity and reductions in the density of 5-HT uptake sites (for review see Curran et al 252 ) and there is evidence to indicate that recovery may remain incomplete for several years.…”

Section: 4-methylenedioxymethamphetamine (Mdma)mentioning

confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

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Section: 4-methylenedioxymethamphetamine (Mdma)mentioning

confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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“…In addition to the acute effects of MDMA to enhance monoamine and ACh release, it is well documented that the repeated administration of MDMA results in a long-term reduction in brain tissue concentrations of 5-HT and reductions in 5-HT reuptake sites in rodents and nonhuman primates (c.f., Ricaurte et al, 2000;Green et al, 2003;Gudelsky and Yamamoto, 2003). On the basis of these neurochemical effects, MDMA is generally viewed to be selectively neurotoxic to 5-HT terminals.…”

Section: Long Term Effects Of Repeated Mdma Administrationmentioning

confidence: 99%

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Gudelsky

Yamamoto

2008

Pharmacology Biochemistry and Behavior

122

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Abstract3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.

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“…The popularity of this drug has given rise to concern, since preclinical research has demonstrated that repeated doses of MDMA can cause serotonergic neurodegeneration in animals (eg Ricaurte et al, 1992Ricaurte et al, , 2000Steele et al, 1994;Green et al, 1995), and there is some evidence that chronic consumption of ecstasy is associated with protracted dysregulation of 5-HT systems in humans. Drug-free ecstasy users have been found to have low levels of 5-HT, and its metabolite 5-HIAA Kish et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Elevated Impulsivity and Impaired Decision-Making in Abstinent Ecstasy (MDMA) Users Compared to Polydrug and Drug-Naïve Controls

Morgan

Impallomeni

Pirona

et al. 2005

Neuropsychopharmacol

111

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(±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals

Cited by 277 publications

References 35 publications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Elevated Impulsivity and Impaired Decision-Making in Abstinent Ecstasy (MDMA) Users Compared to Polydrug and Drug-Naïve Controls

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