Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration

Ricaurte, George A.; DeLanney, Louis E.; Irwin, Ian; Langston, J. William

doi:10.1016/0006-8993(88)91309-1

Cited by 237 publications

(149 citation statements)

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“…These changes can persist for years after the last exposure (Bowyer et al 2003;Taffe et al 2002Taffe et al , 2003Reneman et al 2002;Hatzidimitriou et al 1999;Scheffel et al 1998;Nash and Yamamoto 1992;Slikker et al 1989). The most consistent and prominent findings in the primate brain are reductions in brain serotonin (5-HT), its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), the 5-HT transporter (SERT), and tryptophan hydroxylase (Ricaurte et al 1988a(Ricaurte et al ,b, 1992. In humans, the 5-HT system is also most notably affected, with reduced cerebrospinal fluid levels of 5-HT and 5-HIAA and reduced SERT binding potential in the brain (Steele et al 1994;Buchert et al 2004;McCann et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…In the mammalian brain, 3,4-methylenedioxymethamphetamine (MDMA) induces selective decrements in markers of monoamine neurons as a function of dose, dosing regimen, and species (Ricaurte et al 1988a). These changes can persist for years after the last exposure (Bowyer et al 2003;Taffe et al 2002Taffe et al , 2003Reneman et al 2002;Hatzidimitriou et al 1999;Scheffel et al 1998;Nash and Yamamoto 1992;Slikker et al 1989).…”

Section: Introductionmentioning

confidence: 99%

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MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

2005

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Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, designated as "Ecstasy" if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

2005

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“…This dosing procedure was established in the primate by Ricaurte et al (1985) with 3,4-methylenedioxyamphetamine (MDA, an analog and metabolite of MDMA, Fig. 1b), then extended to MDMA in subsequent studies (Ricaurte et al 1988), and generally results in profound regional depletions in 5-HT, its metabolite 5-hydroxyindoleacetic acid, and decreased binding potential at serotonin transporters (SERT). Most other laboratory groups studying the effects of MDMA in primates also seem to have adopted this dosing procedure (see, for example, Slikker et al 1988Slikker et al , 1989Kleven et al 1989;DeSouza et al 1990;Ali et al 1993;Colado et al 1993;Frederick et al 1998;O'Shea et al 1998;Taffe et al 2002;Bowyer et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Fantegrossi

2006

Psychopharmacology

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Rationale: Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. Objectives: This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of selfadministered MDMA on monoamines. Results: The methylenedioxy amphetamine congeners MDMA, 3, 4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable selfadministration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. Conclusions: Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates.

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“…The administration of MDMA twice per day for four days to either Old World or New World monkeys has been shown in several studies to result in depletion of a number of markers for central 5-HT function. Antemortem observations include decreased concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF (Insel et al 1989;Ricaurte et al 1988a) and in reduced binding of radio-ligands to the 5-HT transporter in PET studies ). Postmortem evidence has shown that the treatment regimen reduces 5-HT and 5-HIAA tissue concentrations, and reduces markers for 5-HT terminals and axons, in a number of brain regions (Ali et al 1993;Insel et al 1989;Ricaurte et al 1988c).…”

mentioning

confidence: 99%

Functional Consequences of Repeated (±)3,4-Methylenedioxymethamphetamine (MDMA) Treatment in Rhesus Monkeys

Taffe

Weed

Davis

et al. 2001

Neuropsychopharmacology

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Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of ( Ϯ )3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.) Recreational use of the psychoactive drug ( Ϯ )3,4,-methylenedioxymethamphetamine (MDMA) has become increasingly popular over the past two decades (Peroutka 1987;Schuster et al. 1998). Although early studies focused on adverse physiological (e.g., hypertension, hyperthermia, hyponatraemia) or psychiatric (mood disorder, aggression) symptoms associated with acute and/or chronic MDMA exposure, recent evidence suggests that chronic MDMA use may also result in lasting disruption of cognitive function. A number of studies have shown that experienced, abstinent MDMA users are impaired on various tests of memory function (Bolla et al. 1998;Curran and Travill 1997;Krystal et al. 1992;Morgan 1999;, even when compared with users of other recreational drugs. The lasting functional effects of MDMA use may be relatively specific to mnemonic processing, since a number of studies have reported that MDMA users who are impaired on memory tasks exhibit normal performance on tests of reaction time, vigilance or selective attention (Krystal et al. 1992;Vollenweider et al. 1998). Additional evidence suggests that the degree of memory impairment in the MDMA user is positively correlated with the number of cumulative exposures to MDMA (Bolla et al. 1998;Parrott and Lasky 1998). Finally, recent studies have demonstrated that electroencephalographic and metabolic (PET) measures of brain function are altered in MDMA users (Dafters et al. 1999;

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Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration

Cited by 237 publications

References 7 publications

MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Functional Consequences of Repeated (±)3,4-Methylenedioxymethamphetamine (MDMA) Treatment in Rhesus Monkeys

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