Amelioration of oxidative kidney damage in offspring by maternal trans-fatty acid exposure in mice by secoisolariciresinol diglucoside. / äºšéº»æœ¨é šç´ å¯¹æ¯é¼ åå¼è„‚è‚ªé ¸æš´éœ²è‡´å­ä»£è‚¾æ°§åŒ–æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Trans-fatty acids (TFAs), primarily derived from the food industry's production processes, have become a globally recognized public health issue due to the detrimental impact they have on human well-being. Secoisolariciresinol diglucoside (SDG) is a polyphenolic compound derived from flax lignans, possessing antioxidative properties. This study aims to investigate the protective effect of SDG on kidney oxidative damage in offspring of mice caused by maternal exposure to TFA during pregnancy and lactation. METHODS: A total of 30 c57BL/6 female rats were randomly divided into 5 groups: a control group, a TFA-exposed group, a low-(TFA+LSDG) group, a medium-(TFA+MSDG) group, and a high-(TFA+HSDG) group (n=6 in each group). With the exception of the control group, the maternal mice in the remaining 4 groups received a daily oral gavage of TFA at a dosage of 60 mg/(kg·BW) throughout the experimental period. The mothers in the control group were administered physiological saline via oral gavage once daily. Meanwhile, the 3 SDG intervention groups were provided with ad libitum access to SDG feed containing 10 mg/kg (low), 20 mg/kg (medium), and 30 mg/kg (high) of SDG. The female mice were conceived overnight. If the vaginal plug appeared in the next morning, the female mice were conceived and included in the experimental stage until the end of the 21th day lactation period. The body weight and kidney mass of offspring were recorded, and the kidney coefficient was calculated. The kidney was detected by HE staining to observe the histopathological changes, and the level of reactive oxidative species (ROS) was detected by fluorescence probe-dihydroethidium (DHE) staining; the expression levels of total superoxide dismutase (T-SOD) and malondialdehyde (MDA) in renal homogenate were detected, and the expression of nuclear factor E2-related fator2 (Nrf2) and hemeoxygenase-1 (HO-1) protein was analyzed by immunohistochemistry (IHC) staining. The mRNA expressions of Nrf2 and HO-1 were detected by real-time PCR, and the protein expression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase-1 (GPx-1), Nrf2 and HO-1 were detected by Western blotting. RESULTS: Compared with the control group, the kidney coefficient in the TFA-exposed group was increased, the morphology and structure of kidney tissue was abnormal; the activity of T-SOD enzyme was decreased, and the content of MDA was increased, the level of ROS was increased; the expressions of Cu/Zn-SOD, Mn-SOD, GPx1 protein were decreased, and the mRNA and protein expressions of Nrf2 and HO-1 were decreased, there were all significant difference (all P<0.05). Compared with the TFA-exposed group, the ROS levels were reduced, and the T-SOD enzyme activity as well as the protein expression of Cu/Zn-SOD, GPx-1, Mn-SOD, Nrf2 and HO-1 were up-regulated in the low, middle and high dose SDG intervention groups; the kidney coefficient and MDA content were decreased in the middle and high dose SDG groups; the Nrf2 mRNA expression in the high dose SDG group was up-regulated, there were all significant difference (all P<0.05). CONCLUSIONS: Maternal exposure to TFA during pregnancy and lactation can lead to oxidative damage in the kidney of offspring, and the SDG intervention may alleviate TFA-induced oxidative damage by up-regulating the expression of Nrf2 and HO-1 signal pathway.

MDA, MDMA, and other "mescaline-like" substances in the US military's search for a truth drug (1940s to 1960s).

This article describes the context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes from the 1940s to the 1960s. Germans first tested mescaline as a "truth drug" in a military context. In the 1940s, the United States military started testing hallucinogenic substances as truth drugs for interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible "speech-inducing" effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4-Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the compounds delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/1954 revealed that some of the "mescaline derivatives" tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. In 1955, the military changed focus to lysergic acid diethylamide (LSD), but some interest in mescaline-like compounds remained for their ability to change mood and habit without interfering with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) whether any of the mescaline derivatives tested were being used operationally.

Disruption of prepulse inhibition by 3,4-methylenedioxymethamphetamine (MDMA): comparison between male and female wild-type and 5-HT(1A) receptor knockout mice.

The aim of this study was to investigate the involvement of serotonin-1A (5-HT(1A)) receptors in the effects of 3,4-methylenedioxymetamphetamine (MDMA) on prepulse inhibition of acoustic startle (PPI) by comparing male and female wild-type (WT) mice and 5-HT(1A) receptor knockout (1AKO) mice. MDMA dose-dependently decreased PPI in male and female mice although female mice were more sensitive at the 100-ms inter-stimulus interval (ISI). In male mice, 10 mg/kg MDMA disrupted PPI in 1AKO but not in WT controls. There was no genotype difference at higher or lower doses of MDMA. In female mice, there was no difference between genotypes at any dose of MDMA. Average startle was reduced by 10 mg/kg and 20 mg/kg MDMA similarly in male and female mice and all genotypes. These results show an involvement of 5-HT(1A) receptors in the effect of MDMA on PPI in male, but not female mice.

The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans. OBJECTIVES: The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR). MATERIALS AND METHODS: Sprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation. RESULTS: HOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (P<0.001). HR responses to MDMA over 6 weeks at both TAs progressively decreased with repeated dosing (P<0.05). TC was significantly higher in both 6-week groups compared to the 1-week groups (P<0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P<0.05) and 5-hydroxyindole acetic acid (5-HIAA; P<0.001) decreased significantly irrespective of TA, while concentrations of dopamine and 5-HT did not change. CONCLUSION: Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.

Development of an on-site screening system for amphetamine-type stimulant tablets with a portable attenuated total reflection Fourier transform infrared spectrometer.

We tried to develop a library search system using a portable, attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectrometer for on-site identification of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) tablets. The library consisted of the spectra from mixtures of controlled drugs (e.g. MDMA and ketamine), adulterants (e.g. caffeine), and diluents (e.g. lactose). In the seven library search algorithms, the derivative correlation coefficient showed the best discriminant capability. This was enhanced by segmentation of the search area. The optimized search algorithm was validated by the positive (n=154, e.g. the standard mixtures containing the controlled drug, and the MDMA/MDA tablets confiscated) and negative samples (n=56, e.g. medicinal tablets). All validation samples except for four were judged truly. Final criteria for positive identification were decided on the basis of the results of the validation. In conclusion, a portable ATR-FT-IR spectrometer with our library search system would be a useful tool for on-site identification of amphetamine-type stimulant tablets.

Antiangiogenic effect of Lygodium flexuosum against N-nitrosodiethylamine-induced hepatotoxicity in rats.

The antiangiogenic effect of Lygodium flexuosum extract was evaluated in Wistar rats intoxicated with N-nitrosodiethylamine (NDEA) in preventive and curative models. In preventive groups, NDEA was administered for 20 weeks. Daily doses of L. flexuosumn-hexane extract (200mg/kg) started 1 week before the onset of NDEA intoxication and continued for 20 weeks. In curative animals, NDEA was administered for 20 weeks followed by treatment with the n-hexane extract of L. flexuosum for 28 days. Rats intoxicated with NDEA had elevated levels of serum gamma-GT, AST, ALT, LDH levels and hepatic MDA and decreased levels of hepatic GSH. When treated with L. flexuosum extract had normal levels of gamma-GT, AST, ALT, LDH levels, hepatic MDA and GSH. NDEA administered rat liver showed an overexpressed levels of angiopoietins 1 (Ang-1) and 2 (Ang-2) and its receptor Tie-2 mRNA. L. flexuosum extract treatment significantly (p

Pociones sexuales. Relación entre alcohol, drogas y sexo / Sex potions. Relationships between alcohol, drugs and sex

A lo largo de la historia, el consumo de drogas y de alcohol ha estado íntimamente ligado a la conducta sexual. A pesar de ello, sin embargo, casi todos los esfuerzos por mejorar la salud sexual y reducir los niveles de consumo de drogas y alcohol se ocupan de ambos problemas como si fueran independientes. Con una disponibilidad potencialmente mayor que nunca de sustancias que tienen efectos relacionados con el sexo, analizar los vínculos entre sexo y consumo de drogas se ha convertido en un factor crítico para tratar ambos problemas. En el presente estudio nos ocupamos de las relaciones entre alcohol, drogas y conducta sexual, incluyendo el consumo de afrodisíacos y facilitadores sexuales, de cómo las sustancias están cada vez más vinculadas a la violencia sexual, y de cómo el propio sexo puede ser un medio para obtener drogas. Analizamos cómo aquellos que consumen drogas y alcohol son sexualmente más activos, tienen más posibilidades de practicar un sexo poco seguro y, por ese motivo, mayor riesgo de enfermedades de transmisión sexual o de embarazos no deseados. Vemos cómo los servicios de asistencia para el consumo de drogas y la salud sexual pueden beneficiarse de un acercamiento entre ambos problemas. Finalmente, en el área de la prevención, estudiamos cómo los servicios de salud sexual pueden utilizar las imágenes relacionadas con la droga para dirigirse a quienes corren el riesgo de contraer enfermedades de transmisión sexual, y cómo esas iniciativas cada vez mayores en la prevención de drogas deben desafiar la imagen sexual de muchas substancias a fin de reducir su atractivo (AU)

Throughout history drug and alcohol use has been intimately linked with sexual behaviour. Despite this however most attempts to improve sexual health and reduce levels of drug and alcohol use treat them as separate issues. With the availability of substances that have sex related effects potentially greater than ever, examining the links between sex and substance use has become a critical factor in addressing both issues. Here we discuss the relationships between alcohol, drugs and sexual behaviour, including the use of drugs as aphrodisiacs and sexual facilitators, how substances are increasingly being implicated in sexual assault, and how sex itself can be a means of obtaining drugs. We examine how those who use alcohol and drugs are more sexually active, more likely to practise unsafe sex, and hence at greater risk of sexually transmitted infections and unwanted pregnancy. We consider how treatment services for substance use and sexual health may benefit from an understanding of each other issues. Finally in the area of prevention, we discuss how sexual health services might utilise drug related imagery to target those at risk of sexual transmitted infections and how those developing drug prevention initiatives must challenge the sexual image of many substances in order to reduce their appeal (AU)

Comparison of pure nicotine- and smokeless tobacco extract-induced toxicities and oxidative stress.

The toxicities and oxidative stress-inducing actions of (-)-nicotine and smokeless tobacco extract (STE), containing equivalent amounts of nicotine, were studied. Toxicities were determined by colony formation assays using Chinese hamster ovary (CHO) cells. Results indicated that nicotine is less toxic than smokeless tobacco extract that contained the same amount of nicotine. The generation of reactive oxygen species, following treatment with smokeless tobacco extract and nicotine, was assessed by measurement of changes in glutathione (GSH) and malondialdehyde (MDA) levels. CHO cells (5 x 10(5) cells/5 ml media) were incubated with 4, 0.8, and 0.08 mg of nicotine and STE containing the same amounts of nicotine. All preparations of smokeless tobacco extract significantly decreased GSH levels and increased MDA generation. However, 0.08 mg of nicotine treatment did not result in a significant change in GSH level, and only 4 mg of nicotine were sufficient to increase MDA generation. Addition of free radical scavenging enzymes, superoxide dismutase (SOD) and catalase (CAT), and an intracellular GSH precursor, N-acetyl-L-cysteine (NAC), replenished the GSH levels in nicotine-treated cells. GSH levels in cells exposed to smokeless tobacco extract containing 4 and 0.8 mg nicotine remained significantly lower than the control with the addition of SOD and CAT. However, co-addition of NAC with smokeless tobacco extract preparations returned the GSH levels to the control level. Lactate dehydrogenase (LDH) activities were measured in the media to establish the membrane damage following exposure to smokeless tobacco extract and nicotine. Treatment of cells with 4 mg nicotine caused a significant increase in LDH activity, which was returned to control level in the presence of the antioxidant enzymes and NAC. Smokeless tobacco extract did not change the LDH activity. http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p434.html

The effect of tea consumption on oxidative stress in smokers and nonsmokers.

While the anticarcinogenic effects of tea in animal models have been reported by several groups, human epidemiological studies examining tea consumption and cancer prevention have produced equivocal results. The beneficial properties of tea to human health may be related to the antioxidant properties of tea components. However, little evidence has been provided that tea consumption can either increase the antioxidant capacity or decrease oxidative stress in humans. In the present study, the effects of tea treatment (green tea) on biomarkers of oxidative stress were investigated in smokers and nonsmokers in two volunteer study groups (one in China and the other in United States). Green tea consumption in both study groups decreased oxidative DNA damage (8-OHdG in white blood cells and urine), lipid peroxidation (MDA in urine), and free radical generation (2, 3-DHBA in urine) in smokers. Nonsmokers (US study group) also exhibited a decrease in overall oxidative stress.

Hyperbaric oxygen therapy attenuates pancreatic microcirculatory derangement and lung edema in an acute experimental pancreatitis model in rats.

This study was designed to investigate hyperbaric oxygen (HBO) therapy as a treatment for managing animals with induced acute pancreatitis. Forty-five anesthetized male Sprague-Dawley rats were studied. A severe acute pancreatitis model was established by combining an intravenous infusion of cerulein (15 microg/kg/h) and an intraductal injection of 0.1 ml of glycodeoxycholic acid (5 mM). Pathology, serum amylase level, pancreatic malondiadehyde levels and water content of the lungs and the pancreas were used to evaluate the severity of disease. Moreover, an in vivo microscopic technique was used to investigate microcirculatory derangement in the pancreas, i.e., flow velocity and leukocytes sticking in postcapillary venules. HBO was delivered in three regimens, i.e., 100% oxygen at 2.5 absolute atmospheric pressure (AAP), 40% oxygen at 2.5 AAP, and 100% oxygen at 1 AAP, 6 h after the initiation of induction of acute pancreatitis. All animals survived until the end of the experiments. HBO significantly improved the pathologic conditions and pancreatic malondiadehyde levels. Concomitantly, it also significantly lessened the severity of lung edema and improved the microcirculatory environment in the pancreas. Our results support the findings that HBO therapy has a beneficial effect on pancreatic microcirculation and lung edema during acute pancreatitis in rats.

Cocaine--stimulus generalization to MDA optical isomers: a reevaluation.

It has already been demonstrated that the psychoactive agent 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) produces effects that are both hallucinogen-like and amphetamine or stimulant-like in animals. Hallucinogenic activity is associated primarily with the R(-)-isomer of MDA whereas stimulant activity is primarily associated with the S(+)-isomer. Because a previous report indicates that S(+)MDA fails to substitute for cocaine in rats trained to discriminate cocaine from vehicle, and because these findings are inconsistent with the purported stimulant nature of S(+)MDA, we reinvestigated the effect of both MDA isomers in rats. In this investigation, S(+)MDA doses of 1.25 and 1.5 mg/kg were found to produce > 80% cocaine-appropriate responding in rats trained to discriminate 8 mg/kg of cocaine from saline. However, consistent with a previous report, R(-)MDA resulted only in partial generalization. These new results support the hypothesis that the optical isomers of MDA produce distinguishable stimulus effects in rats and that S(+)MDA is the more stimulant isomer of MDA.

Use of drugs at 'raves'.

Widespread use of drugs at the currently popular 'raves' has caused concern principally because of an increasing number of cases of serious toxicity and even death. The availability and use of drugs at raves, mainly in the Edinburgh area, have been investigated and self-reported use of drugs compared with results of urine screening. Use of Ecstasy and LSD have been confirmed and there is evidence to support the use of Khat. A new preparation, Herbal Ecstasy, is readily available at Edinburgh raves and appears to be widely used. All urines tested positive for one or more drugs or drug metabolites and in general analytical results correlated well with self-reported use of drugs.

Peroxide-cyclooxygenase interactions in postasphyxial changes in retinal and choroidal hemodynamics.

To test the role of reactive oxygen species and cyclooxygenase products in the retinal hemodynamic changes induced by asphyxia, we measured retinal (RBF) and choroidal blood flows (ChBF), malondialdehyde (MDA), prostaglandin E2 (PGE2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) in 1- to 3-day-old pigs treated with saline, the free radical scavengers U-74389F or high-dose allopurinol, the cyclooxygenase inhibitors ibuprofen or indomethacin, or the thromboxane synthase blocker CGS-13080 before and 5 and 60 min after a 5-min period of asphyxia. In saline-treated animals, RBF and ChBF increased 5 min after asphyxia and decreased at 60 min. The increases in RBF and ChBF at 5 min postasphyxia were slightly attenuated by cyclooxygenase blockers and free radical scavengers but not by thromboxane synthase inhibition, whereas all drugs prevented the decreases at 60 min. MDA, TxB2, PGE2, and 6-keto-PGF1 alpha increased 5 min after asphyxia; at 60 min, PGE2 and 6-keto-PGF1 alpha returned to nearly preasphyxial levels, but MDA and TxB2 continued to increase. Cyclooxygenase inhibition prevented the asphyxia-induced rise in MDA, and the free radical scavengers prevented that of prostanoids. In isolated eyecup preparations, H2O2 and cumene hydroperoxide constricted retinal arteries; this effect was blocked by cyclooxygenase and thromboxane synthase inhibitors. The data suggest that during oxidative stresses reactive oxygen species are generated from the cyclooxygenase pathway and, in turn, also activate the synthesis of thromboxane; the latter mediates the oxidative stress-induced ocular vasoconstriction that might trigger the neovascularization of retinopathy of prematurity.

Effect of flunarizine and nimodipine on the decrease in tryptophan hydroxylase activity induced by methamphetamine and 3,4-methylenedioxymethamphetamine.

The effect of calcium channel blockers on the decrease in central tryptophan hydroxylase (TPH) activity and serotonin (5-HT) concentration induced by repeated large doses of methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received four or five injections of METH (10 or 15 mg/kg) or MDMA (10 mg/kg) at 6-h intervals, and were sacrificed 18 to 20 h or 1 week after the last administration. Flunarizine (30 mg/kg) prevented the decline in cortical and neostriatal TPH activity induced by MDMA, but failed to alter the effect of METH. The effect of flunarizine on the METH- and MDMA-induced changes in cortical 5-HT and 5-hydroxyindoleacetic acid concentrations paralleled the changes in enzyme activity. Nimodipine, diltiazem or TA-3090 failed to prevent the MDMA- and the METH-induced decline in TPH activity or in 5-HT and 5-hydroxyindoleacetic acid content. Because haloperidol failed to mimic the protective action of flunarizine, it is unlikely that flunarizine exerts its action by blocking the dopamine D-2 receptors. This study suggests that calcium influx may participate in the MDMA-induced decline in central TPH activity, and that the mechanism by which MDMA and METH decreases TPH activity differs.

Prevention of selenite cataract by vitamin C.

Studies have been conducted to determine the efficacy of vitamin C in the prevention of cataracts induced by selenite. Administration of the latter to rat pups results in the development of advanced cataracts within 5 days. Treatment with ascorbate had a significant preventive effect. The observations indicate that selenite cataract is due to an oxidative stress to the lens. In addition, the findings are in conformity with our view that ascorbate functions as an anticataractogenic substance.

Prepulse inhibition of the acoustic startle response is disrupted by N-ethyl-3,4-methylenedioxyamphetamine (MDEA) in the rat.

N-Ethyl-3,4-methylenedioxyamphetamine (MDEA) is a derivative of methylenedioxyamphetamine (MDA), a substituted amphetamine with demonstrated abuse liability. MDA, MDEA and a third substituted amphetamine, methylenedioxymethamphetamine (MDMA), all produce a destructive action on central serotonin neurons and appear to induce some similar behavioral effects. The present study investigated the effects of racemic MDEA and its stereoisomers on prepulse inhibition of the acoustic startle response, a behavioral model of sensorimotor gating that is sensitive to psychostimulant drugs. Rats were subjected to 122 dB[A] acoustic noises, some of which were preceded by a weak 80 dB[A] prepulse noise. In vehicle-injected control rats, the prepulse induced a significant decrease in startle amplitude when compared to trials in which startle stimuli were not preceded by prepulses. Administration of racemic MDEA (0.3-10.0 mg/kg) and (+) MDEA (0.1-3.0 mg/kg) induced a significant attenuation in prepulse inhibition, while (-) MDEA (0.3-10.0 mg/kg) did not. Racemic MDMA (0.3-10.0 mg/kg) produced similar though not significant effects. These results confirm a stimulant-like behavioral effect of MDEA despite its relatively modest effects on dopamine markers, and support findings that the (+) stereoisomers of substituted amphetamines are more potent than tha (-) stereoisomers in producing psychostimulant-like biochemical and behavioral effects.

Effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on central serotonergic and dopaminergic systems of the rat.

The influence of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic and dopaminergic systems of the rat after a single or multiple injections was studied. MDE (10 mg/kg) produced a significant decrease in the concentration of 5-hydroxytryptamine (5-HT) 1 hr later in the frontal cortex and the hippocampus without affecting the concentration of 5-hydroxyindoleacetic acid (5-HIAA) or tryptophan hydroxylase (TPH) activity. Hypothalamic and neostriatal concentrations of 5-HT, 5-HIAA, dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unaffected, as well as the neostriatal TPH and tyrosine hydroxylase (TH) activities. However, 3 hr after the MDE injection, the serotonergic variables including TPH activity were decreased in most of the brain areas examined. The dopaminergic system remained unaffected, except for a significant reduction in neostriatal DOPAC concentrations. The changes in transmitter concentrations after a single injection were dose dependent; the maximum depletion in TPH activity was reached with a 10 mg/kg dose. The administration of multiple doses of MDE caused greater decreases in TPH activity and 5-HT concentrations 3 hr after the treatment than did a single injection; in addition, a partial recovery from multiple administrations occurred by 18 hr. The effects of MDE on DA and its metabolites were transient, and neostriatal TH activity was not altered. This study demonstrates that MDE primarily affects the central serotonergic system, as reported for its congeners 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. It does, however, produce less neurotoxicity as judged by its lower potency on the dopaminergic and the serotonergic systems as well as the recovery occurring in these systems.

Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain.

3,4-Methylenedioxymethamphetamine (MDMA) is a recently popularized recreational drug, although some have advocated its psychotherapeutic potential. Since the pharmacology of MDMA is largely uncharacterized, the stereochemical profiles of MDMA and some of its homologs were derived on inhibition of synaptosomal uptake of [3H]monoamines and compared to those of amphetamine and the hallucinogenic phenylisopropylamine 2,5-dimethoxy-4-methylamphetamine (DOM). In contrast to the 5-fold stereoselectivity observed with amphetamine, only the S-(+) enantiomer of MDMA and 3,4-methylenedioxyamphetamine (MDA) inhibited [3H]dopamine uptake into striatal synaptosomes. Neither stereoisomer of the alpha-ethyl homolog of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), inhibited [3H]dopamine uptake. The two stereoisomers of amphetamine and the MDMA-related compounds were equipotent in inhibiting [3H]norepinephrine uptake into hypothalamic synaptosomes. Both stereoisomers of MDMA, MDA and MBDB were potent inhibitors of [3H]serotonin uptake into hippocampal synaptosomes, but only S-(+)-amphetamine produced an appreciable inhibition of [3H]serotonin uptake. Neither stereoisomer of DOM inhibited synaptosomal uptake of any [3H]monoamine. These results suggest that MDMA and its homologs may be more closely related to amphetamine rather than to DOM in their biochemical mode of action. The pronounced effects of the methylenedioxy-substituted compounds on [3H]serotonin and [3H]norepinephrine uptake implicate these neurotransmitters in the pharmacological effects of these drugs.

Toxicity of methylenedioxymethamphetamine (MDMA) in the dog and the rat.

Methylenedioxymethamphetamine (MDMA) was administered to dogs and rats orally once a day for a 28-day period to evaluate the morphological and neuropathological effects. Major clinical signs associated with the administration of MDMA in the dog included circling, depression, dilated pupils, hyperactivity, rapid breathing, and salivation. Major clinical signs in the rat included hyperactivity, excitability, piloerection, exophthalmos, and salivation. Gross observations at necropsy in the dog possibly related to administration of the test article included reduced testicular size (one high and one medium dose) and prostatic enlargement in two high-dose animals. No gross lesions were seen in the rats at necropsy. The medium- and the high-dose groups in both sexes in both the rats and the dogs gained significantly less weight than the control and low-dose groups. Food consumption decreased the first week for the high- and medium-dose groups, but a significant reversal toward more normal consumption was noted in the following weeks in both the rats and the dogs. Hematologic, clinical chemistry, and urinalysis values did not appear to be affected by the administration of the test article in the dog. In the rat clinical pathology variables showing a trend to decrease with dose included urinary pH, blood urea nitrogen, glucose, creatinine (females), lactate dehydrogenase (LDH) (females), and chloride. Clinical pathology variables showing a trend to increase with dose included total white blood cell count and phosphorus. Microscopically, testicular atrophy was present in one medium-dose and two high-dose male dogs. Prostatic hyperplasia was present in two high-dose male dogs. No test article-related lesions were seen in the brains of either species.