MDMA (Ecstasy) precipitation of panic disorder.

The authors describe three patients whose panic disorder began during recreational use of MDMA (Ecstasy) and was subsequently complicated by agoraphobic avoidance that continued autonomously after cessation of the drug. Their panic disorder responded well to serotoninergic antidepressant drugs. Theoretical and practical implications are discussed.     

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.     

Reduced 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Initiated Oxidative DNA Damage and Neurodegeneration in Prostaglandin H Synthase-1 Knockout Mice

The neurodegenerative potential of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and underlying mechanisms are under debate. Here, we show that MDMA is a substrate for CNS prostaglandin H synthase (PHS)-catalyzed bioactivation to a free radical intermediate that causes reactive oxygen species (ROS) formation and neurodegenerative oxidative DNA damage. In vitro PHS-1-catalyzed bioactivation of MDMA stereoselectively produced free radical intermediate formation and oxidative DNA damage that was blocked by the PHS inhibitor eicosatetraynoic acid. In vivo, MDMA stereoselectively caused gender-independent DNA oxidation and dopaminergic nerve terminal degeneration in several brain regions, dependent on regional PHS-1 levels. Conversely, MDMA-initiated striatal DNA oxidation, nerve terminal degeneration, and motor coordination deficits were reduced in PHS-1 +/- and -/- knockout mice in a gene dose-dependent fashion. These results confirm the neurodegenerative potential of MDMA and provide the first direct evidence for a novel molecular mechanism involving PHS-catalyzed formation of a neurotoxic MDMA free radical intermediate.     

Ecstasy (MDMA) exposure and neuropsychological functioning: a polydrug perspective.

Ecstasy (MDMA) is a popular drug that can act as a selective serotonin neurotoxin in several species. The goal of the present study was to examine the relationship between ecstasy exposure and cognitive functioning after controlling for other drug use and demographic variables. Furthermore, we assessed whether gender was a moderator of the relationship between cognitive functioning and ecstasy use. Data were collected from 31 men and 34 women with a wide range of ecstasy use (17 marijuana users with no ecstasy use and 48 ecstasy users ranging from low to heavy use). Participants were interviewed and administered a battery of neuropsychological tests. The primary finding was that ecstasy exposure was significantly related to poorer verbal learning and memory ability in a dose-dependent manner, while no such relationship was observed between ecstasy exposure and executive functioning or attentional ability. Gender was found to significantly moderate the relationship between ecstasy consumption and design fluency. These results suggest primary memory dysfunction among abstinent recreational ecstasy users. This finding is consistent with reports of hippocampal vulnerability, particularly among heavy users.     

Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user

ARTICLE ABSTRACT: The authors found that striatal levels of serotonin and those of its metabolite 5-hydroxyindoleacetic acid were severely depleted by 50 to 80% in brain of a chronic user of methylenedioxymethamphetamine (MDMA) whereas concentrations of dopamine were within the normal control range. Our data suggest that MDMA exposure in the human can cause decreased tissue stores of serotonin and therefore some of the behavioral effects of this drug of abuse could be caused by massive release and depletion of brain serotonin.     

Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat

It was recently demonstrated that acute administration of 3,4-methylenedioxymethamphet-amine (MDMA, "Ecstasy") is capable of counteracting haloperidol-induced catalepsy in rats. The present study was done with another psychostimulant, S-(-)-cathinone. In these experiments, 32 male Sprague-Dawley rats, 225 +/- 25 g, were used. They were divided into three groups. All groups received 0.5 mg/kg haloperidol in normal saline (s.c.) as a first injection. Then 30 min later each group received either isotonic phosphate-buffered saline, 1 mg/kg S-(-)-cathinone, or 2.5 mg/kg (RS)-MDMA (s.c.) as a second injection. The results of descent latency on both the horizontal bar and vertical grid showed that S-(-)-cathinone or (RS)-MDMA upon acute administration induces a strong anticataleptic activity (P < 0.0001) compared to rats treated with haloperidol plus vehicle. The effect of both drugs was later masked upon subchronic administration (days 2-7, 26-29). This is probably due to sensitization of cataleptic behavior. However, when the same groups of rats were tested on day 8 in a different task, i.e., open-field, they showed a significant difference (P < 0.05). The detailed mechanism of the observed strong anticataleptic activity of S-(-)-cathinone (which is considered a potent dopamine releaser) requires further investigation.     

MDMA (Ecstasy/Molly) Use Among African Americans: Patterns of Initiation

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy/molly) use among African Americans has increased over the last two decades, yet there has been little examination into how African Americans initiate their use of the drug. This study aimed to fill this knowledge gap by exploring the initiation experiences of African Americans and their narrative accounts of the circumstances surrounding their MDMA onset. Audiotapes of in-depth interviews were transcribed, coded, and thematically analyzed. Analyses revealed the presence of initiation patterns that contrast somewhat with those found in other groups of MDMA users. This study adds to the limited research on African American MDMA use and sheds light on why some African Americans decide to start using the drug. The findings provide insights to prevention specialists, harm reduction workers, and treatment providers who work with African American drug users.     

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.     

Acute and Chronic Acetazolamide Administration in DBA and C57 Mice: Effects of Age

The clinical utility of the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is limited because of rapid development of tolerance to its effects. Tolerance is thought to develop as a result of glial cell proliferation and/or increased CA synthesis. DBA mice, susceptible to audiogenic seizures (AGSs) in an age-dependent manner, have increased CA activity as compared with C57 (non-audiogenic seizure susceptible) mice at 21 and 110 days of age. The present work utilized ACTZ to help determine the relationship between increased CA activity in brain and AGSs in DBA mice. Also, minimal electroshock seizure threshold (EST) was measured at various ages in DBA and C57 mice to determine age-related changes in CNS excitability. EST was significantly lower in DBA as compared with C57 mice at 18 days and between 40 and 115 days of age, suggesting that DBA mice remain hyperexcitable to electrical stimulation after they develop resistance to AGSs. ACTZ ED50s against maximal electroshock seizures (MES) were significantly higher in DBA as compared with C57 mice at 26,36, and 115 days of age. This finding correlates with higher CA activity in this strain at 110 days of age, noted previously. However, at 21 days of age, when CA activity is also higher in DBA versus C57 mice, there were no significant differences in ACTZ ED50s against MES between the strains. ACTZ ED50s against AGSs in DBA mice were considerably lower than ACTZ ED50s against MES in either strain, suggesting that a particular fraction of CA is intimately involved in the production of AGSs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anticonvulsant Activity of Phenobarbital and Valproate Against Maximal Electroshock in Mice During Chronic Treatment with Caffeine and Caffeine Discontinuation

We evaluated the protective activity (expressed as ED₅₀, values in mg/kg) of phenobarbital (PB, 120 min before testing) and valproate (30 min) alone or combined with caffeine in male mice with seizures induced by maximal electroshock (MES). Both antiepilep-tic drugs (AEDs) were administered by intraperitoneal (i.p.) injection in a single dose to mice receiving intraperitoneal caffeine either in a single dose 30 min before the test or as pretreatment every 12 h for 3 and 14 days. In addition, we determined the ED⁵⁰, values of the AEDs 24 and 72 h after 14–day treatment with caffeine. Finally, we studied the influence of a challenge dose of caffeine, injected in mice 24 and 72 h after 14 days of treatment with caffeine, on the protective activity of PB or VPA. Caffeine in a single dose of 23.1 mg/kg reduced the anticonvulsant effect of PB. Its protective activity was further impaired after 3 and 14 days of caffeine treatment. The ED⁵⁰, for VPA was significantly increased both by the single dose of caffeine and by chronic treatment. The anticonvulsant activity of PB and VPA measured 24 and 72 h after 14–day treatment with caffeine did not differ from control values, but a challenge dose of caffeine injected 24 or 72 h after daily injections for 14 days resulted in a significant reduction in the protective activity of both AEDs. Measurement of the total plasma levels of caffeine, VPA, and PB did not suggest pharmacokinetic interactions as an explanation for our results. Our results indicate that chronic caffeine exposure may progressively reduce the antiepileptic potency of VPA and PB.     

Neurotoxic effects of MDMA (“ecstasy”) administration to neonatal rats

3,4-Methylenedioxymethamphetamine damages fine serotonergic fibers and nerve terminals in adult organisms. Developing animals seem to be less susceptible to this effect, possibly due to a lack of drug-induced hyperthermia. We tested this hypothesis by producing hyperthermia in neonatal rats for 2 h after each of twice-daily MDMA (10 mg/kg s.c.) or saline injections administered from postnatal days 1–4. Other drug-treated and control litters were maintained at normothermic temperatures following injection. Changes in forebrain serotonergic innervation were assessed at postnatal day 25 (serotonin transporter binding and serotonin levels), postnatal day 60 (serotonin transporter binding), and 9 months of age (serotonin transporter immunohistochemistry). We also determined the influence of MDMA treatment on apoptotic activity by means of immunohistochemistry for cleaved caspase-3 at postnatal day 5. The hippocampus showed significant MDMA-related reductions in serotonergic markers at postnatal day 25 and postnatal day 60. At 9 months, there was no effect of prior MDMA exposure on serotonin transporter-immunoreactive fiber density in the hippocampus; however, significant reductions in fiber density were observed in two neocortical areas and a hyperinnervation was found in the caudate-putamen and nucleus accumbens shell. MDMA treatment also produced a two-fold increase in the number of cleaved caspase-3-immunoreactive cells in the rostral forebrain and hippocampus. All of these effects were completely independent of pup body temperature. These findings demonstrate that neonatal MDMA administration exposure stimulates apoptotic cell death in various forebrain areas and also leads to a long-term reorganization of the forebrain serotonergic innervation. Consequently, offspring of MDMA-using women may be at heightened risk for abnormal neural and behavioral development.     

Neural correlates of MDMA ("Ecstasy")-induced social interaction in rats

The popular drug 3,4 methylenedioxymethamphetamine (MDMA, "Ecstasy", "the Love Drug") produces feelings of love and closeness in humans and induces analogous prosocial and antiaggressive effects in laboratory animals. Here we examined the specific brain regions that may be involved in these prosocial effects. Male Wistar rats were pretreated with a moderate dose of MDMA (5 mg/kg) or vehicle and then either kept alone in a familiar test chamber for 60 min (groups MDMA-ALONE and VEHICLE-ALONE) or allowed to engage in social interaction in the familiar test chamber with an unfamiliar same-sex conspecific for 60 min (groups MDMA-SOCIAL and VEHICLE-SOCIAL). Rats in the MDMA-SOCIAL group showed much greater overall social interaction than rats in the VEHICLE-SOCIAL group, with microanalysis revealing increased general investigation of other rats but decreased anogenital sniffing. Analysis of neural activation across 39 brain regions using Fos immunohistochemistry showed the following results: (1) VEHICLE-SOCIAL and VEHICLE-ALONE groups did not differ in Fos expression, indicating that a social context per se did not affect Fos expression, (2) MDMA-treated groups showed significantly increased Fos expression relative to VEHICLE treated groups in 30 brain regions, (3) the MDMA-SOCIAL group showed augmented Fos expression relative to the MDMA-ALONE group in six brain regions including the caudate-putamen (medial), medial preoptic area, paraventricular thalamic nucleus, central amygdala, ventromedial hypothalamic nucleus, and the medial amygdala (posterodorsal), and (4) the MDMA-SOCIAL group (but not the MDMA-ALONE group) showed augmented Fos expression relative to the VEHICLE groups in the nucleus accumbens, ventral tegmental area and periaqueductal grey. These results indicate that a moderate dose of MDMA given in a social context causes considerably greater brain activation than the same dose given to solitary rats. This activation involves specific neural circuits that are known to regulate affiliative behavior, perhaps by modulating the incentive value of social stimuli. A possible role for the neuropeptide oxytocin in mediating the prosocial effects of MDMA is discussed.     

Motor Neurons Pathology After Chronic Exposure to MPTP in Mice

Neurotoxicity Research - The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different...     

Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats

Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.     

咖啡因慢性干预对小鼠实验性自身免疫性脑脊髓炎影响的观察

目的：探讨不同剂量咖啡因慢性干预对小鼠实验性自身免疫性脑脊髓炎（EAE）的影响及其分子免疫学机制。方法：C57BL／6小鼠随机分为CFA阴性对照组,EAE阳性对照组,咖啡因饮水干预组（1mg·k-1,10mg·kg-1,30mg·kg-1）。使用髓鞘少突胶质细胞糖蛋白35-55（MOG35-55）抗原诱导小鼠EAE模型,咖啡因干预至EAE造模后第20天与对照组小鼠同期处死为止。观察小鼠行为学变化、中枢炎症细胞浸润和损害程度、检测中枢细胞因子IL-17、IFN—γ、TGF—β的mRNA表达含量。结果：咖啡因干预组,特别是30mg·kg-1组的病情严重程度减轻,中枢炎症细胞浸润程度下降,促炎因子表达降低,抑炎因子表达上升。结论：慢性咖啡因干预,可通过降低促炎因子的表达,升高抑炎因子的表达,减轻小鼠EAE的炎症损伤。     

Enzymatic–nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA,VMAT2, HSP70, and apoptosis as biomarkers for MDMA (Ecstasy) neurotoxicity

3,4‐Methylenedioxymethamphetamine (MDMA)‐induced neurotoxicity leads to the formation of quinone metabolities and hydroxyl radicals and then to the production of reactive oxygen species (ROS). We evaluated the effect of a single dose of MDMA (20 mg/kg, i.p.) on the enzymatic and nonenzymatic cellular antioxidant defense system in different areas of rat brain in the early hours (<6 hr) of the administration itself, and we identified the morphological expressions of neurotoxicity induced by MDMA on the vulnerable brain areas in the first 24 hr. The acute administration of MDMA produces a decrease of reduced and oxidized glutathione ratio, and antioxidant enzyme activities were significantly reduced after 3 hr and after 6 hr in frontal cortex. Ascorbic acid levels strongly increased in striatum, hippocampus, and frontal cortex after 3 and 6 hr. High levels of malonaldehyde with respect to control were measured in striatum after 3 and 6 hr and in hippocampus and frontal cortex after 6 hr. An immunohistochemical investigation on the frontal, thalamic, hypothalamic, and striatal areas was performed. A strong positive reaction to the antivesicular monoamine transporter 2 was observed in the frontal section, in the basal ganglia and thalamus. Cortical positivity, located in the most superficial layer was revealed only for heat shock protein 70 after 24 hr. © 2009 Wiley‐Liss, Inc.     

咖啡因对小鼠空间学习记忆能力及有关脑区记忆相关蛋白CREB表达的影响

目的：研究咖啡因对小鼠空间学习记忆能力以及有关脑区记忆相关蛋白——环腺苷酸应答元件结合蛋白（CREB）表达的影响。方法：C57BL／6J小鼠45只随机分成3组：咖啡因小剂量组（10mg·kg^-1）、咖啡因大剂量组（50mg·kg^-1）及生理盐水对照组，均腹腔给药。采用Morris水迷宫评价空间记忆能力及Western blot检测CREB的表达量。结果：与大剂量组及生理盐水对照组相比，咖啡因小剂量组定位航行实验逃避潜伏期显著缩短；空间搜索实验穿越原平台位置的次数显著增多；海马组织CREB表达显著增加。结论小剂量咖啡因能够提高小鼠空间学习记忆能力，且增加海马区CREB的表达。