"Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.
"Hence, clinically relevant comparisons of the behavioral and pharmacokinetic effects of MDMA must include a consideration of the dose range and dosing schedules used. For example, human studies of the behavioral and pharmacokinetic effects of MDMA have been limited to the lower portion of the abused MDMA dose range [for review, see Parrott (2005)] and this is likely due to the neurotoxic effects of MDMA reported in rodents and nonhuman primates (Sarkar and Schmued, 2010). We sought to follow up on our previous work with oral MDMA in the baboon (Mueller et al., 2011) to characterize the behavioral effects of MDMA across a wide dose range (0.32–7.8 mg/kg) as well as to determine the plasma concentration-over-time profiles of MDMA and its major metabolites in the same subjects. "
[Show abstract][Hide abstract] ABSTRACT: (±)-3,4-Methylenedioxymethamphetamine HCl (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 (0.32 - 7.8 mg/kg) were administered via an intragastric catheter to adult male baboons (N=4). Effects of MDMA on food-maintained responding were assessed over a 20-h period, while untrained behaviors and fine-motor coordination were characterized every 30 min until 3 h post-administration. Levels of MDMA and metabolites in plasma were measured in the same animals (N=3) following dosing on a separate occasion. MDMA decreased food-maintained responding over the 20-h period, and systematic behavioral observations revealed increased frequency of bruxism as the dose of MDMA was increased. Drug blood level determinations showed no MDMA after the lower doses of MDMA tested (0.32-1.0 mg/kg) and modest levels following higher MDMA doses (3.2-7.8 mg/kg). High levels of 3,4-dihydroxymethamphetamine (HHMA) were detected after all doses of MDMA, suggesting extensive first-pass metabolism of MDMA in the baboon. The present results demonstrate that MDMA administered via an intragastric catheter produced behavioral effects that have also been reported in humans. Similar to humans, blood levels of MDMA following oral administration may not be predictive of the behavioral effects of MDMA. Metabolites, particularly HHMA, may play a significant role in the behavioral effects of MDMA.
Journal of Pharmacology and Experimental Therapeutics 03/2013; 345(3). DOI:10.1124/jpet.113.203729 · 3.97 Impact Factor
"Brain serotonin systems have been associated with the rewarding effects of MDMA, and serotonin antagonists block MDMA-induced CPP (Bilsky and Reid, 1991). Moreover, MDMA acts primarily by releasing 5-HT from presynaptic 5-HT terminals (Schmidt et al., 1987), which eventually leads to a persistent loss of brain serotonergic neuron functioning and a reduction in 5-HT and 5-HIAA levels (Battaglia et al., 1987; Sarkar and Schmued, 2010). Previous studies have shown that different protocols of maternal separation can induce alterations in brain serotonergic systems, such as decreased 5-HT levels in the ventral striatum (Kosten et al., 2004), increased hippocampal 5- HT1A and 5-HT1B receptors and cortical 5-HT2 receptors and lower levels of 5-HT1A receptors in the raphe nuclei (Vázquez et al., 2002), and higher SERT levels in the amygdala (Vicentic et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: The early neonatal stage constitutes a sensitive period during which exposure to adverse events can increase the risk of neuropsychiatric disorders. Maternal deprivation (MD) is a model of early life stress that induces long-term behavioural and physiological alterations, including susceptibility to different drugs of abuse. In the present study we have used the conditioned place preference (CPP) paradigm to address the influence of MD on the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in adolescent animals of both sexes. We have previously observed in adolescent rats that MD induces modifications in the serotonergic and endocannabinoid systems, which play a role in the rewarding effects of MDMA. In light of this evidence, we hypothesized that MD would alter the psychobiological consequences of exposure to MDMA. Neonatal Wistar rats underwent MD (24h, on PND9) or were left undisturbed (controls). The animals were conditioned with 2.5mg/kg MDMA during the periadolescent period (PND34-PND43) and were tested in the open-field test at the end of adolescence (PND 60). Animals were sacrificed on PND 68-75 and levels of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid were measured in the striatum, hippocampus and cortex, while the expression of hippocampal CB1 cannabinoid receptor (CB1R) and circulating levels of corticosterone and leptin were also measured. Control males showed CPP after administration of MDMA. However, no MDMA-induced CPP was detected in control females or MD males, and MD had no effect on open field activity in any group. A reduction in striatal and cortical 5-HT levels, increased expression of hippocampal CB1R and a marked trend towards higher circulating leptin levels were observed in MDMA-treated MD males. Our results demonstrate for the first time that MD reduces the rewarding effects of MDMA in a sex-dependent manner. We propose that this effect is related, at least in part, with alterations of the serotonergic and cannabinoid systems.
"Whereas cocaine has similar affinities at DAT, SERT and NET (Bennett et al., 1995), MDMA has 10-fold higher affinity at SERT compared to DAT (Steele et al., 1987; Battaglia et al., 1988), perhaps explaining the lower rate of acquisition (Schenk et al., 2007) and the weaker reinforcing strength of MDMA compared to cocaine (Lile et al., 2005). Consistent with its high affinity and selectivity for SERT, MDMA exposure has been associated with alterations in the 5-HT system (for reviews see Sprague et al., 1998; Green et al., 2003; Gudelsky and Yamamoto, 2008; Schenk, 2009; Sarkar and Schmued, 2010). In vitro examination following MDMA administration showed lower binding in 5-HT uptake sites but not DA or NE uptake sites measured via in vitro receptor autoradiography (e.g., Battaglia et al., 1987, 1988, 1991; Insel et al., 1989; Scanzello et al., 1993; Schenk et al., 2007; Biezonski and Meyer, 2010) as well as SERT internalization (Kittler et al., 2010; Kivell et al., 2010) compared to cocaineinduced elevations in membranous SERT expression (Kittler et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Cocaine self-administration alters brain dopaminergic and serotonergic function primarily in mesolimbic and prefrontal brain regions whereas 3,4-methylenedioxymethamphetamine (MDMA) self-administration predominately alters brain serotonergic function in a more widespread distribution across cortical regions. We previously reported that, compared to drug-naïve rhesus monkeys, self-administration of cocaine but not MDMA was associated with increased serotonin transporter (SERT) availability in two mesolimbic regions, the caudate nucleus and putamen, as measured by positron emission tomography (PET) using the SERT-specific ligand [(11)C]-3-amino-4(2-dimethylamino-methyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB). The goal of the present study was to extend this comparison between cocaine and MDMA self-administration to SERT availability in cortical regions, which have been shown previously to be affected in human drug abusers and are associated with executive function. PET studies using [(11)C]DASB were conducted in adult male rhesus monkeys with a history of cocaine (mean intake = 742.6 mg/kg) or MDMA (mean intake = 121.0 mg/kg) self-administration, and drug-naïve controls (n = 4/group). Regions of interest were drawn for several cortical (prefrontal, temporal, parietal, occipital and midcingulate) and subcortical (thalamus, amygdala and hippocampus) areas. Cortical SERT availability was significantly higher in monkeys with a cocaine self-administration history compared to controls whereas MDMA self-administration resulted in lower levels of SERT availability. These data extend our previous findings indicating that cocaine and MDMA self-administration differentially alter SERT availability in subcortical and cortical regions, which may have implications for development of treatment drugs.
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