MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons

Battaglia, George; Yeh, S.Y.; Souza, Errol B. De

doi:10.1016/0091-3057(88)90155-4

Cited by 294 publications

(150 citation statements)

References 19 publications

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“…As expected, MDMA treatment caused significant reductions in all neurochemical measures in both brain areas at the 1-week time point, and pretreatment with citalopram almost completely prevented these reductions. SERT levels showed some degree of recovery between 1 and 10 weeks after dosing, which is consistent with the previous findings of Battaglia et al (1988). However, in contrast to the 1-week results, the CITAL/MDMA group unexpectedly did not differ from the SAL/MDMA group with respect to SERT binding measured at 10 weeks post-treatment.…”

Section: Discussionsupporting

confidence: 90%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, SpragueDawley rats (N ¼ 67) received MDMA (4 Â 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drug's effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

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Section: Discussionsupporting

confidence: 90%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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“…In addition, no influence of cannabis use on several conditions of ASR was observed. Previous animal data have shown that application of MDMA causes a selective and sustained reduction of 5-HT levels in the brain (Stone et al, 1986;Commins et al, 1987;Schmidt, 1987;Battaglia et al, 1988;Insel et al, 1989;Wilson et al, 1989;Ali et al, 1993;Scheffel et al, 1998;Hatzidimitriou et al, 1999;Taffe et al, 2001), and there is also some evidence for selectively lowered serotonergic neurotransmission in chronic MDMA users (McCann et al, 1994. Acute 5-HT depletion decreased PPI in animals and humans consistently (Phillips et al, 2000; Fletcher et al, Figure 2 Habituation curve diagrammed as mean amplitude of 116-dBpulse-alone trials in six blocks and a single initial 116-dB-pulse-alone trial (means7SEM).…”

Section: Resultsmentioning

confidence: 99%

“…In animals, administration of MDMA produces a rapid and marked release of serotonin (5-HT) via inhibition and reversal of the 5-HT transporter (Rudnick and Wall, 1992). There is convincing evidence that MDMA produces a substantial and sustained long-term neurotoxic loss of 5-HT nerve terminals with an associated depletion of 5-HT in several brain regions of rats, guinea pigs, and several species of nonhuman primates (Stone et al, 1986;Commins et al, 1987;Schmidt, 1987;Battaglia et al, 1988;Insel et al, 1989;Wilson et al, 1989;Ali et al, 1993;Scheffel et al, 1998;Hatzidimitriou et al, 1999;Taffe et al, 2001). Studies of MDMA use in humans have also shown selective decrements in cerebrospinal fluid (CSF) concentrations of 5-hydroxy indoleacetic acid (5-HIAA) as a marker for central serotonergic depletion, with no alterations in CSF homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolites of dopamine and norepinephrine, respectively (McCann et al, 1994.…”

Section: Introductionmentioning

confidence: 99%

Prepulse Inhibition and Habituation of Acoustic Startle Response in Male MDMA (‘Ecstasy’) Users, Cannabis Users, and Healthy Controls

Quednow

Kühn

Hoenig

et al. 2004

Neuropsychopharmacol

107

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Chronic administration of 3,4-methylenedioxymethamphetamine (MDMA) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and nonhuman primates. Despite the broad database concerning the selective serotonergic neurotoxicity of recreational MDMA consumption by humans, controversy still exists with respect to the question of whether the well-known functional consequences of these neurotoxic effects, such as memory impairment, were caused by chronic 5-HT deficiency. Habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) can be used as a marker of central serotonergic functioning in rodents and humans. Thus, we investigated the functional status of the central serotonergic system in chronic but abstinent MDMA users by measuring PPI and habituation of ASR. PPI and habituation of ASR were measured in three groups. The first group (MDMA group) included 20 male drug-free chronic users of MDMA; the second group (cannabis group) consisted of 20 male drug-free chronic users of cannabis; and the third group (healthy controls) comprised 20 male participants with no history of illicit drug use. Analysis revealed significantly increased PPI of MDMA users compared to those of cannabis users and healthy controls. Cannabis users and healthy controls showed comparable patterns of PPI. There were no differences in habituation among the three groups. These results suggest that the functional consequences of chronic MDMA use may be explained by 5-HT receptor changes rather than by a chronic 5-HT deficiency condition. Use of cannabis does not lead to alterations of amplitude, habituation, or PPI of ASR.

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“…Most studies using comparable treatment regimens also report sustained reduction in serotonin content and other markers of serotonin nerve terminals (see review by Lyles and Cadet 2003). The extent to which these changes reverse is controversial: some studies show restoration of serotonin content in rodents after extremely long recovery times (Battaglia et al 1988;Lew et al 1996;Sabol et al 1996;Scanzello et al 1993), and some assert that nerve terminals are not damaged (Wang et al 2005). The loss of serotonin in the present study occurred with only modest temperature increases.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

et al. 2006

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Rationale 3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT). Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist. Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment. Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later. Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females.

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MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons

Cited by 294 publications

References 19 publications

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Prepulse Inhibition and Habituation of Acoustic Startle Response in Male MDMA (‘Ecstasy’) Users, Cannabis Users, and Healthy Controls

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

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