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.

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.

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.

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.

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.

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.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) produces long-term reductions in brain 5-hydroxytryptamine in rats.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) was administered to rats as a single 40 mg/kg injection s.c. or 40 mg/kg s.c. every second day for 4 injections. Sixteen days following the last injection rats were killed. MDMA produced significant depletions of 5-HT and its metabolite 5-HIAA in the hippocampus and the frontal cortex. 5-HT was depleted to 30% of control value in the hippocampus following a single dose. 5-HT levels were not affected in the hypothalamus, suggesting differential effects on brain 5-HT systems. DA levels in the hypothalamus were significantly increased while NE levels in the frontal cortex were decreased to 73% of control following 4 doses of MDMA. MDMA, therefore, produces long-term depletions in 5-HT which suggests that it may act as a neurotoxin at 5-HT neurons in the brain of rats.