In vivo absolute quantification of carnosine in the vastus lateralis muscle with H MRS using a surface coil and water as internal reference.

Objective: To standardize a method for H MRS intramuscular absolute quantification of carnosine in the thigh, using a surface coil and water as internal reference.

Materials And Methods: Carnosine spectra were acquired in phantoms (5, 10, and 15 mM) as well as in the right gastrocnemius medialis (GM) and right vastus lateralis (VLM) muscles of young team sports athletes, using volume (VC) and surface (SC) coils on a 3 T scanner, with the same receiver gain. Water spectra were used as internal reference for the absolute quantification of carnosine.

Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents.

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug-plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations.

Methylphenidate and impulsivity: a comparison of effects of methylphenidate enantiomers on delay discounting in rats.

Rationale: Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g.

Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release.

The current study aimed to elucidate the role of pharmacokinetic (PK) parameters and neurotransmitter efflux in explaining variability in (±) 3, 4-methylenedioxymethamphetamine (MDMA) self-administration in rats. PK profiles of MDMA and its major metabolites were determined after the administration of 1.0 mg/kg MDMA (iv) prior to, and following, the acquisition of MDMA self-administration.

Behavioral effects and pharmacokinetics of (±)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) after intragastric administration to baboons.

(±)-3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a popular drug of abuse. We aimed to characterize the behavioral effects of intragastric MDMA in a species closely related to humans and to relate behavioral effects to plasma MDMA and metabolite concentrations. Single doses of MDMA (0.

Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species.

Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated.

Identifying the serotonin transporter signal in Western blot studies of the neurotoxic potential of MDMA and related drugs.

A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and related drugs (fenfluramine, p-chloroamphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after substituted amphetamine treatment. The purpose of this study was to collect Western blot data using the same SERT antibody used in those studies, but with positive and negative controls to identify the SERT protein signal. A 63-68 kDa band that had the regional distribution expected of rat brain SERT, was decreased by 5,7-DHT, and was absent in SERT KO animals was identified as the SERT protein.

Altered pain responses in abstinent (±)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users.

Rationale: (±)3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has potential to damage brain serotonin (5-HT) neurons in humans. Brain 5-HT neurons play a role in pain modulation, yet little is known about long-term effects of MDMA on pain function. Notably, MDMA users have been shown to have altered sleep, a phenomenon that can lead to altered pain modulation.

Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.

The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined.

Metabolism and disposition of 3,4-methylenedioxymethamphetamine ("ecstasy") in baboons after oral administration: comparison with humans reveals marked differences.

The baboon is potentially an attractive animal for modeling 3,4-methylenedioxymethamphetamine (MDMA) effects in humans. Baboons self-administer MDMA, are susceptible to MDMA neurotoxicity, and are suitable for positron emission tomography, the method most often used to probe for MDMA neurotoxicity in humans. Because pharmacokinetic equivalence is a key feature of a good predictive animal model, we compared the pharmacokinetics of MDMA in baboons and humans.

Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity.

3,4-Methylenedioxymethamphetamine (MDMA)'s O-demethylenated metabolite, 3,4-dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol-thioether metabolites (e.g., 5-N-acetylcystein-S-yl-HHMA) that mediate MDMA neurotoxicity.

Dopamine is not essential for the development of methamphetamine-induced neurotoxicity.

It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of L-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature.

Sleep apnea in young abstinent recreational MDMA ("ecstasy") consumers.

Background: Methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular recreational drug of abuse and a selective brain serotonin neurotoxin. Functional consequences of MDMA neurotoxicity have defied ready characterization. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing in which brain serotonin dysfunction may play a role.

Sleep deprivation differentially impairs cognitive performance in abstinent methylenedioxymethamphetamine ("Ecstasy") users.

Methylenedioxymethamphetamine (MDMA; "Ecstasy") is a popular recreational drug and brain serotonin (5-HT) neurotoxin. Neuroimaging data indicate that some human MDMA users develop persistent deficits in brain 5-HT neuronal markers. Although the consequences of MDMA-induced 5-HT neurotoxicity are not fully understood, abstinent MDMA users have been found to have subtle cognitive deficits and altered sleep architecture.

Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity.

The mechanism by which the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals.

Direct comparison of (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") disposition and metabolism in squirrel monkeys and humans.

The present study compared the disposition and metabolism of the recreational drug (+/-) 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in squirrel monkeys and humans because the squirrel monkey has been extensively studied for MDMA neurotoxicity. A newly developed liquid chromatography-mass spectrometric procedure for simultaneous measurement of MDMA, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine, and 3,4-methylenedioxyamphetamine was employed. In both humans and squirrel monkeys, a within-subject design permitted testing of different doses in the same subjects.

Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma.

Characterizing the formation of metabolites of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") in different species (rat, squirrel monkey, and human) may provide insight into mechanisms of MDMA neurotoxicity. Two prominent MDMA metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), are conjugated with glucuronic or sulfuric acid, but reference standards are not available; therefore, quantification is only possible after conjugate cleavage. Different concentrations of HHMA and HMMA were obtained in human, squirrel monkey, and rat plasma specimens when acid or enzymatic cleavage was performed.

Simultaneous liquid chromatographic-electrospray ionization mass spectrometric quantification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its metabolites 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine and 3,4-methylenedioxyamphetamine in squirrel monkey and human plasma after acidic conjugate cleavage.

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a psychoactive drug with abuse liability and neurotoxic potential. Specimen preparation of a recently presented LC-MS assay with electrospray ionization for quantifying MDMA and its main metabolites in squirrel monkey plasma was modified to include acidic hydrolysis to obtain total 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxy-methamphetamine. Method re-validation for squirrel monkey plasma and full validation for human plasma showed selectivity for all analytes.

Liquid chromatographic-electrospray ionization mass spectrometric assay for simultaneous determination of 3,4-methylenedioxymethamphetamine and its metabolites 3,4-methylenedioxyamphetamine, 3,4-dihydroxymethamphetamine, and 4-hydroxy-3-methoxymethamphetamine in rat brain.

3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug with abuse liability and neurotoxic potential. Mechanisms by which MDMA produces behavioral and neurotoxic effects have yet to be elucidated. By measuring concentrations of MDMA and its metabolites in relevant brain sites, it may be possible to gain insight into mechanisms underlying MDMA actions.

Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine ("ecstasy") users: relationship to cognitive performance.

Background: (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related.

Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses.

At certain doses, the psychoactive drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs.

Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users.

Background: Studies in abstinent methamphetamine (METH) users have demonstrated reductions in brain dopamine transporter (DAT) binding potential (BP), as well as cognitive and motor deficits, but it is not yet clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. This study was conducted to further investigate potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods with [(11)C]WIN 35428.

Methods: Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.

Effects of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) on sleep and circadian rhythms.

Abuse of stimulant drugs invariably leads to a disruption in sleep-wake patterns by virtue of the arousing and sleep-preventing effects of these drugs. Certain stimulants, such as 3,4-methylenedioxymethamphetamine (MDMA), may also have the potential to produce persistent alterations in circadian regulation and sleep because they can be neurotoxic toward brain monoaminergic neurons involved in normal sleep regulation. In particular, MDMA has been found to damage brain serotonin (5-HT) neurons in a variety of animal species, including nonhuman primates, with growing evidence that humans are also susceptible to MDMA-induced brain 5-HT neurotoxicity.

Validated liquid chromatographic-electrospray ionization mass spectrometric assay for simultaneous determination of 3,4-methylenedioxymethamphetamine and its metabolites 3,4-methylenedioxyamphetamine, 3,4-dihydroxymethamphetamine, and 4-hydroxy-3-methoxymethamphetamine in squirrel monkey plasma.

3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug with neurotoxic potential. Pharmacokinetic data of MDMA and its metabolites may shed light on the mechanism of MDMA neurotoxicity. An LC-MS assay with electrospray ionization (ESI) is presented for quantifying MDMA and its metabolites 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) in squirrel monkey plasma.