Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration

Abstract

MDMA (3,4-methylenedioxymethamphetamine or “ecstasy”) is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.     

The neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on serotonin, dopamine, and GABA-ergic terminals: an in-vitro autoradiographic study in rats

Damage to serotonin (5-HT) terminals following doses of 3,4-methylenedioxymethamphetamine (MDMA) is well documented, and this toxicity is thought to be related to dopamine release that is potentiated by the 5-HT(2A/2C) agonist effects of the drug. Although MDMA and methamphetamine (METH) have some similar dopaminergic activities, they differ in their 5-HT agonistic properties. It is reasoned that the study of the resultant toxicity following equimolar doses of MDMA and METH on both dopamine and 5-HT terminals should offer a comparison of the ability of these drugs to induce neurotoxicity. In order to measure the toxic effects to the brain, rats were given equimolar doses of MDMA (40 mg/kg/day) and METH (32 mg/kg/day) in subcutaneously implanted osmotic minipumps for a period of 5 days, and in-vitro autoradiography using [3H]-paroxetine, [3H]-mazindol, [3H]-methylspiperone, and [3H]-flunitrazepam, was performed on brain sections. The results showed that METH was more toxic to 5-HT terminals than MDMA in forebrain regions, including the anterior cingulate, caudate nucleus, nucleus accumbens, and septum. METH was also more toxic than MDMA to dopamine terminals in the habenula, and posterior retrosplenial cortex. Therefore, we find that METH was more toxic to 5-HT and dopamine terminals in specific brain regions in both pre and post-synaptic sites following continuous equimolar dosing.     

Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users

Summary The majority of recreational Ecstasy/MDMA users (90–98%) also take cannabis. This co-drug usage is often viewed as a methodological confound, which needs to be removed statistically. Here we take a rather different approach, and debate the potential complexities of their psychobiological interactions. The ring-substituted amphetamine derivate MDMA (3,4-methylendioxymethamphetmaine, or ‘Ecstasy’) is a powerful CNS stimulant, whereas cannabis is a relaxant. Their co-usage may reflect opposing effects in three psychobiological areas: arousal, body temperature, and oxidative stress. Firstly MDMA is alerting whereas cannabis is sedating. Secondly MDMA is hyperthermic whereas cannabis is hypothermic. Thirdly MDMA increases oxidative stress whereas cannabinoids are antioxidant. Hence cannabis may modulate the acute and sub-acute reactions to MDMA, reduce the acute hyperthermia induced by MDMA, and ameliorate the oxidative stress caused by MDMA. The limited empirical evidence on each topic will be critically examined. In terms of chronic effects each drug is functionally damaging, so that polydrug users generally display cumulative neurobiological impairments. However in certain aspects their neuropsychobiological effects may interactive rather than additive. In particular, the combined use of cannabis and MDMA may have rather different neuropsychobiological implications, than their separate usage. In order to investigate these potential complexities, future research will need better empirical data on the exact patterns of co-drug usage.     

The effect of MDMA (3,4-methylenedioxymethamphetamine) on the 5-HT synthesis rate in the rat brain: an autoradiographic study

The effect of MDMA (3,4-methylenedioxymethamphetamine), a psychotropic amphetamine derivative, treatment on the rate of serotonin (5-hydroxytryptamine; 5-HT) synthesis in the rat brain was studied by autoradiography using α- -methyl- -tryptophan method. Three different treatment protocols were compared to the control (saline) treated rats: (1) rats treated twice with 10 mg/kg every 12 h (20 mg/kg total) and injected tracer for the synthesis measurements 15 h later; (2) rats treated with four injections of 5 mg/kg every 12 h (20 mg/kg total) and injected tracer for the synthesis measurement 17 h after the last dose; and (3) rats given eight injections of 5 mg/kg every 12 h for four days (40 mg/kg) and used in the synthesis study 14 days after the last dose. Results showed a significant decrease in the rate of synthesis in the majority of cerebral structures examined in the 10 mg/kg group. In contrast the group receiving the same total amount (20 mg/kg) of MDMA but over two days (4×5 mg/kg) showed a significant increase in 5-HT synthesis in comparison to controls. The 5-HT synthesis rates measured 14 days after the last dose (four days, 8×5 mg/kg) were significantly reduced. The findings suggest that MDMA can produce either an increase or a decrease in the 5-HT synthesis a short time after a total dose of 20 mg/kg depending on the dose fractionation. However, 14 days after total dose of 40 mg/kg given over four days the synthesis rate was significantly reduced in many brain structures. The latter suggests a possible effect of the MDMA neurotoxicity on the serotonergic neurons, in addition to a possible influence on 5-HT synthesis via a feedback mechanism.     

Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a widely used recreational drug. Despite an increase in the number of fatalities related to its use, no definite therapeutic method has been established thus far. In the present study, risperidone's ability to attenuate MDMA-induced hyperthermia and its mechanism of action were investigated in rats. The pharmacological effect of MDMA was evaluated using microdialysis. In the body temperature experiment, administration of risperidone before and after MDMA administration significantly suppressed MDMA-induced hyperthermia in a dose-dependent fashion. Furthermore, risperidone completely inhibited MDMA-induced hyperthermia at a low ambient temperature. Moreover, pretreatment with ritanserin, ketanserin, or R-96544, all of which are 5-HT_2A-receptor antagonists, significantly prevented MDMA-induced hyperthermia. On the other hand, pretreatment with WAY-100635 (a 5-HT_1A receptor antagonist), SB 206553 (a 5-HT_2B/2C receptor antagonist), or SB 242084 (a 5-HT_2C receptor antagonist) did not prevent MDMA-induced hyperthermia. Pretreatment with haloperidol, which blocks the dopamine (DA) receptors D₂ and D₁, significantly prevented MDMA-induced hyperthermia. However, sulpiride and L-741626, which are D₂ receptor blockers, did not prevent MDMA-induced hyperthermia. Pretreatment with SCH 23390 (a D₁ receptor antagonist) significantly prevented MDMA-induced hyperthermia. Furthermore, postadministration of ritanserin, haloperidol, and SCH23390 reversed MDMA-induced hyperthermia. These results demonstrate that the mechanism underlying the suppression of MDMA-induced hyperthermia by risperidone is primarily based on the drug's potent 5-HT_2A receptor blocking effect, and to a lesser extent, on its D₁ receptor blocking effect. A microdialysis study showed that when MDMA (10 mg/kg) was subcutaneously (s.c.) injected into the rats, the DA and serotonin (5-HT) levels in the anterior hypothalamus of the rats increased approximately 10- and 50-fold, respectively, as compared to their preadministration levels. These increases in the DA and 5-HT levels after MDMA injection were significantly suppressed by pretreatment with risperidone (0.5 mg/kg). This suggested that both the DA and 5-HT systems were involved in the induction of hyperthermia by MDMA. Taken together, the present study's results indicate that risperidone may be an effective drug for the treatment of MDMA-induced hyperthermia in humans.     

Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a very popular drug of abuse. This has led to new intense concerns relevant to its nefarious neuropsychiatric effects. These adverse events might be related to the neurotoxic effects of the drug. Although the mechanisms of MDMA-induced neurotoxicity remain to be fully characterized, exposure to the drug can cause acute and long-term neurotoxic effects in animals and nonhuman primates. Recent studies have also documented possible toxic effects in the developing fetus. Nevertheless, there is still much debate concerning the effects of the drug in humans and how to best extrapolate animal and nonhuman primate data to the human condition. Herein, we review the evidence documenting the adverse effects of the drug in some animal models. We also discuss possible mechanisms for the development of MDMA neurotoxicity. Data supporting deleterious effects of this drug on the developing fetus are also described. Much remains to be done in order to clarify the molecular and biochemical pathways involved in the long-term neuroplastic changes associated with MDMA abuse.     

Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine

3,4-Methylenedioxymethamphetamine ("Ecstasy," MDMA) and fenfluramine, widely used by humans, are potent brain serotonin (5-HT) neurotoxins in animals. Thus, there is concern that humans previously exposed to these amphetamine derivatives may have incurred brain 5-HT neurotoxicity. However, assessing the status of brain 5-HT neurons in the living organism is challenging. To determine whether MDMA- and/or fenfluramine-induced 5-HT neurotoxicity can be detected during life using neuroendocrine methods, groups of monkeys previously treated with neurotoxic regimens of MDMA or fenfluramine, along with saline-treated controls, underwent neuroendocrine challenge with the direct 5-HT agonist and 5-HT-releasing drug, m-chlorophenylpiperazine (m-CPP). Animals treated 2 weeks previously with MDMA exhibited a nonsignificant reduction in the prolactin response to m-CPP. In contrast, monkeys treated 3 1/2 years previously with MDMA or 2 years previously with fenfluramine exhibited significantly increased prolactin responses to m-CPP. No significant differences in cortisol concentrations were noted between groups at any time point. These data indicate that neuroendocrine challenge with m-CPP is capable of detecting substituted amphetamine-induced 5-HT neurotoxicity in living primates, but that the recency of drug exposure is an important consideration. Changes in the neuroendocrine response to m-CPP over time in animals with substituted amphetamine-induced neurotoxicity may be related to aberrant 5-HT reinnervation of the basal forebrain that occurs over time in monkeys previously treated with neurotoxic doses of MDMA or fenfluramine.     

Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, serotonin and dopamine content, and [35S]GTPgammaS binding in adult rats

Recreational use of methylenedioxymethamphetamine (MDMA) has dramatically increased among juveniles and young adults of child-bearing age, and the potential for fetal exposure has increased. For this reason, it is surprising that comparatively few studies have assessed the long-term impact of early MDMA exposure on serotonin (5-HT) and dopamine (DA) neurotransmitter systems. The purpose of this study was to determine whether repeated exposure to MDMA during the preweanling period would cause long-term changes in 5-HT and DA functioning. Rats were treated with saline or 20 mg/kg MDMA (two injections per day) from postnatal day (PD) 11-20. At PD 90, rats were killed, and their dorsal striatum, prefrontal cortex, and hippocampus were removed. 5-HT and DA content, as well as their metabolites, were measured using HPLC. In addition, cAMP-dependent protein kinase A (PKA) activity and agonist-stimulated [35S]GTPgammaS binding was assayed using tissue homogenates from each brain region. Results indicated that early MDMA exposure caused a decrease in PKA activity and 5-HT content in the prefrontal cortex and hippocampus while increasing the efficacy of 5-HT1A receptors as measured by agonist-stimulated [35S]GTPgammaS binding. Additionally, DA content was reduced in the dorsal striatum and prefrontal cortex. These data indicate that early MDMA exposure has long-term effects on the 5-HT and DA neurotransmitter systems that may be mediated, at least partially, by changes in 5-HT1A receptor sensitivity.     

Neuropsychological effects of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) in recreational users

While neuropsychological studies on 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) users have been emerging, results have been inconsistent, possibly due to methodological issues. The current study examined the performance of 22 recreational MDMA users compared to 28 age, education, and IQ comparable normal control subjects on a comprehensive battery of neuropsychological tests. Results revealed no significant differences in cognitive functioning between the MDMA users and normal controls. However, greater use of MDMA was associated with poorer scores on several measures of nonverbal memory, and greater frequency users (> or = 50 times) evidenced significantly lower scores on 2 of 3 nonverbal memory tests compared to lesser frequency users (< 50 times). Our results suggest that a subgroup of MDMA patients, specifically heavy MDMA users, evidence declines in nonverbal (visual) memory, however, other cognitive areas appear to be spared.     

Neuroendocrine abnormalities in recreational ecstasy (MDMA) users: is it ecstasy or cannabis?

BACKGROUND: The purpose of this study was to investigate neuroendocrine function in ecstasy (3,4-methylenedioxymethamphetamine = MDMA) users and controls. METHODS: Prolactin response to d-fenfluramine was assessed in abstinent ecstasy users with concomitant use of cannabis only (n = 24, male/female 13/11) and in two control groups: healthy nonusers (n = 13, female) and exclusive cannabis users (n = 7, male). RESULTS: Prolactin response to d-fenfluramine was slightly blunted in female ecstasy users. Both male user samples exhibited a weak prolactin response to d-fenfluramine, but this was weaker in the group of cannabis users. Baseline prolactin and prolactin response to d-fenfluramine were associated with the extent of previous cannabis use. CONCLUSIONS: Endocrinological abnormalities of ecstasy users may be closely related to their coincident cannabis use. Cannabis use may be an important confound in endocrinological studies of ecstasy users and should be looked for more systematically in future studies.     

Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth,litter effects or injection stress

Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed. Males, but not females, exposed to MDMA had longer latencies and more errors in the Cincinnati water maze compared to males of the other treatments. In the Morris water maze (210 cm pool, 10x10 cm platform), the MDMA animals were impaired relative to all other treatments during acquisition. Only the MDMA females showed deficits when the platform was shifted to a new location, however, both MDMA males and females were impaired when the location of the platform was again shifted and a reduced platform (5x5 cm) used. No differences were observed in the ability to swim a straight channel, locate a platform with a cue, or the endocrine response to forced swim among the treatment groups. No differences were seen between animals injected with saline and those only weighed. The data suggest that factors, such as growth retardation, multiple injections, or the composition of the litter, do not affect the development of learning and memory impairments resulting from P11 to 20 MDMA exposure. The large litter approach offers a novel method to control for undernutrition during the preweaning period in rodents.     

Serotonergic modulation of 3,4-methylenedioxymethamphetamine (MDMA)-elicited reduction of response rate but not rewarding threshold in accumbal self-stimulation

In a fixed interval 5-s rate-frequency function paradigm with rats, 3,4-methylenedioxymethamphetamine (MDMA; 0.5, 2 and 4 mg/kg) dose-dependently decreased response rate for nucleus accumbens self-stimulation while both D-amphetamine (0.3 and 1 mg/kg) and cocaine (5 and 15 mg/kg) increased response rates. The highest dose of MDMA caused a cessation of responding in many of the rats tested, but in those rats that continued to respond a significant reduction in frequency threshold for self-stimulation was seen. Cocaine and amphetamine dose-dependently reduced frequency threshold in all rats tested. The non-specific serotonin antagonist, methysergide (5 mg/kg), reversed the inhibitory effects of MDMA on response rates and caused all rats to respond following MDMA (4 mg/kg). Methysergide did not affect MDMA's threshold-lowering properties and when administered alone methysergide had no effect on self-stimulation. These results suggest serotonergic involvement in the performance but not reinforcement-modulating effect of MDMA in the self-stimulation paradigm.     

Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): Evidence from using CuZn-superoxide dismutase transgenic mice

The subacute and long-term biochemical effects of methylenedioxymeth-amphetamine (MDMA) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. Non-transgenic (Non-Tg) mice showed significant decreased in striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels both at 24 h and at 2 weeks after a single injection of MDMA (50 mg/kg). Heterozygous SOD-Tg mice showed DA depletion only at the 24 h time point. In contrast, homozygous SOD-Tg mice show no DA or DOPAC depletion at either the 24 h or at the 2 week time points. Moreover, three injections of MDMA (50 mg/kg) given 24 h apart also caused marked reduction of striatal DA and DOPAC in Non-Tg mice when these substances were measured 2 weeks after the last MDMA injection. That injection schedule also caused small decreases in DA levels in the heterozygous animals but no changes in the homozygous mice; DOPAC levels were not affected in the heterozygous nor in the homozygous SOD-Tg mice. Furthermore, the multiple injection schedule caused significant decreases in DA and DOPAC in female Non-Tg mice but not in the two strains of transgenic mice. Neither the single dose nor the multiple dose schedule of MDMA injections affected striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIM)levels in any of the three strains of mice. These results support previous observations that MDMA-induced biochemical effects are observed in the DA systems of mice, whereas these effects are seen in the 5-HT systems of rats. The present observations also document for the first time a role for the production of superoxide radicals in these effects of MDMA. These mice are an important tool for dissecting pathways involved in drug-induced neurotoxicity. © 1995 Wiley-Liss, Inc. 1

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography.

The widely abused "designer" drug MDMA (3,4-methylenedioxymethamphetamine) has been shown to cause marked and long-lasting changes in brain serotonergic systems. The present study uses quantitative in vitro autoradiography of 3H-paroxetine labeled 5-HT uptake sites to assess the time-dependent effects of MDMA on 5-HT neurons in specific neuroanatomic loci. Following treatment with MDMA (20 mg/kg, b.i.d. for 4 days), marked decreases in 5-HT uptake sites were observed in a number of brain regions known to receive projections of 5-HT neurons. These regions included cerebral cortex, caudate nucleus, hippocampus, nucleus accumbens, olfactory tubercle, superior and inferior colliculi, geniculate nuclei, and most thalamic nuclei. In contrast, other areas such as the septal nuclei and some thalamic nuclei which also receive 5-HT projections were not substantially affected by this drug. In most regions, decreases in 5-HT uptake sites occurred within 24 hours of the last dose of MDMA and persisted at the 2 week time point. Some regions such as dorsal striatum exhibited a time-dependent reduction with greater reductions occurring at 2 weeks rather than immediately following the MDMA treatment regimen. The density of 5-HT uptake sites in other regions such as endopiriform nucleus and substantia nigra at the 2 week versus 18 hour time point indicated some degree of region-specific recovery. Regions which demonstrated no significant reduction in 5-HT uptake sites included the dorsal and median raphe nuclei, ventral tegmental area, central grey, interpeduncular nucleus, locus coerulus, pontine reticular formation and cerebellum. Likewise, regions containing 5-HT axons of passage (e.g., indusium griseum and lateral hypothalamus) appeared to be insensitive to the neurotoxic effects of MDMA on 5-HT neurons. Furthermore, the neurotoxic effects of MDMA showed specificity in that the catecholamine neurons labeled by 3H-mazindol were unaffected by the treatment regimen. These data indicate that the preferential degeneration of serotonergic neurons by MDMA is mediated primarily at 5-HT terminal regions, whereas regions containing 5-HT perikarya and axons of passage remain relatively unaffected. In addition, the observed time-dependent reductions and recovery of 5-HT uptake sites which were detected within 2 weeks of the treatment regimen in certain brain regions suggest region-specific differences in recovery of 5-HT systems from MDMA-induced lesion.     

Sub-chronic nandrolone treatment modifies neurochemical and behavioral effects of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in rats

Misuse of anabolic-androgenic steroids (AASs) is increasing, and appears to have much in common with the use of substances known to induce drug dependence. Moreover, persons who abuse AASs also tend to abuse other psychotropic drugs such as amphetamine or 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The aim of this study was to investigate whether nandrolone (5 x 5 or 5 x 20 mg/kg) pre-exposure modulates the acute neurochemical and behavioral effects of amphetamine (1mg/kg) and MDMA (5 mg/kg) in rats. Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from samples collected from the nucleus accumbens (NAc) by in vivo microdialysis. The behavior of the animals was recorded on videotapes, from which it was later rated. Our results demonstrate that sub-chronic treatments with supraphysiological doses of nandrolone attenuate dose-dependently the increase in extracellular DA concentration evoked by amphetamine or MDMA. The lower dose of nandrolone attenuated MDMA-induced increase in 5-HT-levels, while the higher dose potentiated it. Analysis of the behavioral data suggests that effects of the amphetamine and MDMA are dose-dependently attenuated by AAS-treatment, paralleling DA results. In conclusion, the results of this study show that AAS-pre-treatment is able to modulate the reward-related neurochemical and behavioral effects of amphetamine and MDMA.     

Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: evidence from an 18-month longitudinal functional magnetic resonance imaging study.

BACKGROUND: Working memory processing in ecstasy (3,4-methylenedioxymethamphetamine) users is associated with neural alterations as measured by functional magnetic resonance imaging. Here, we examined whether cortical activation patterns change after prolonged periods of continued use or abstinence from ecstasy and amphetamine. METHODS: We used an n-back task and functional magnetic resonance imaging in 17 ecstasy users at baseline (t(1)) and after 18 months (t(2)). Based on the reported drug use at t(2) we separated subjects with continued ecstasy and amphetamine use from subjects reporting abstinence during the follow-up period (n = 9 and n = 8, respectively). RESULTS: At baseline both groups had similar task performance and similar cortical activation patterns. Task performance remained unchanged in both groups. Furthermore, there were no detectable functional magnetic resonance imaging signal changes from t(1) to t(2) in the follow-up abstinent group. However, the continuing users showed a dose-dependent increased parietal activation for the 2-back task after the follow-up period. CONCLUSIONS: Our data suggest that ecstasy use, particularly in high doses, is associated with greater parietal activation during working memory performance. An altered activation pattern might appear before changes in cognitive performance become apparent and, hence, may reflect an early stage of neuronal injury from the neurotoxic drug ecstasy.     

Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: interaction with exposure in adulthood

This study determined whether developmental and adult 3,4-methylenedioxymethamphetamine (MDMA) exposures in rats have interactive effects on body temperature, learning, other behaviors, and monoamine concentrations in the hippocampus, prefrontal cortex, and striatum. Learning was assessed in the Cincinnati water maze (CWM), Morris water maze (MWM), and novel object recognition (NOR). On acquisition trials in the MWM, significant differences from developmental MDMA exposure were found on latency, cumulative distance, path length, and angle of first bearing to the goal, but the early and adult MDMA exposure group performed no worse than the developmental-only MDMA group. In the reversal trials, however, an interaction was seen: latency to the goal, cumulative distance, and angle of first bearing were increased in animals treated both developmentally and in adulthood with MDMA compared with those treated only developmentally. Other tests (elevated zero maze, CWM, NOR, and open-field activity) did not show an interaction, nor did hippocampal concentrations of serotonin or dopamine. However, several behavioral tests showed neonatal MDMA effects, including increased errors in the CWM, reduced time spent with a new object in the NOR test, and reduced locomotor activity in the open-field. By contrast, adult MDMA decreased the number of entries into open quadrants of the elevated zero maze. Litter effects were controlled by treating litter as the experimental unit and using mixed models repeated measures analyses. Correlational analyses suggested that the MWM reversal interaction involves multiple monoamine changes. The results indicate that developmental MDMA exposure can interact with adult exposure to interfere with some aspects of learning.     

Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals. Serotonin plays a role in numerous functional systems in the CNS. Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine, and cognitive disorders might be expected in humans following damage of the central serotonergic system. In recent years, the questions of possible functional disorders following ecstasy-induced neurotoxicity were addressed in several cross-sectional studies with drug users. In this review we summarize and evaluate the quality of design of these studies. Despite large methodological problems, evidence accumulates in favor of persisting brain damage in ecstasy users resulting in subtle cognitive deterioration. Findings of relatively low memory performance associated with heavy ecstasy use are highly consistent across different studies and user populations. In addition, low performance in tests of higher executive function were reported in some but not all studies. The important questions about progression, persistence, or reversibility of damage after long periods of abstinence have to be addressed in future studies with longitudinal design.     

Long-lasting effects of (+/-)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system function in humans.

BACKGROUND: Fifteen (+/-)3,4-Methylenedioxymethamphetamine (MDMA) users, who did not show other drug dependencies or prolonged alcohol abuse, and 15 control subjects were included in the study. METHODS: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation. RESULTS: MDMA users showed significantly reduced PRL and CORT responses in comparison with control subjects at 3 weeks (respectively, p < .001; p < .005). The responses of PRL to D-fen were unmodified at 12 months after prolonged abstinence and were significantly reduced in comparison with controls (p < .001). In contrast, CORT responses in MDMA users were restored after 12 months of abstinence, with significantly higher responses to D-fen, in comparison with 3-week responses (p < .05). MDMA users' high scores on the Novelty Seeking (NS) scale on the Tridimensional Personality Questionnaire (TPQ) appeared unchanged by long-term abstinence. In contrast, Buss Durkee Hostility Inventory (BDHI) (Buss and Durkee 1957) direct and guilt scores decreased significantly after 12 months of abstinence. PRL AUCs at 12 months were inversely correlated with the measures of MDMA exposure (r = -.538). CONCLUSIONS: Our data indicate long-lasting 5-HT system impairment in abstinent MDMA users although the hypothesis of serotonergic changes attributable to a premorbid condition cannot be excluded. CORT restored responses to D-fen at 12 months, and the correlation of neuroendocrine changes with MDMA exposure suggest that the neuroendocrine impairment may be due to a partially reversible neurotoxic action of MDMA on the human brain.     

Rewarding effects of 3,4-methylenedioxymethamphetamine ("Ecstasy") in dominant and subordinate OF-1 mice in the place preference conditioning paradigm

We tested the ability of 3,4-methylenedioxymethamphetamine (MDMA) to induce conditioned place preference (CPP) in dominant and subordinate OF-1 mice subjected to cohabitation and repeated sessions of agonistic confrontation, as well as in non-confronted mice. We selected doses of MDMA (2, 6, 10 mg/kg) previously reported to induce CPP in mice and we measured expression of c-Fos evoked by the treatments in non-confronted mice. MDMA induced c-Fos protein in several corticolimbic regions involved in drug-induced reward. Mice were exposed to brief sessions of agonistic confrontation on 5 consecutive days. Determinations of circulating hormones and drug conditioning tests were carried out on completion of the encounters. The results of hormone assays indicated that dominant mice had higher serum concentrations of testosterone, but lower levels of corticosterone, than submissive mice. Post-conditioning tests after drug conditioning (4 injections of MDMA or saline on alternate days) showed that MDMA significantly produced CPP at doses of 2 and 6 mg/kg, but not at 10 mg/kg, an inverted U-shaped pattern of conditioning that was invariable in non-confronted, dominant and subordinate mice. These results demonstrate that the endocrine and behavioural correlates linked to social status and social stress in mice are not paralleled by significant changes in the rewarding efficacy of MDMA in the CPP paradigm under the specific conditions tested.