Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. RESULTS: The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. CONCLUSION: The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA

3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. OBJECTIVE: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of “interspecies scaling” to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. RESULTS: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1–2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10–20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. CONCLUSIONS: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks

Should patients with hip joint prosthesis receive antibiotic prophylaxis before dental treatment?

The safety committee of the American Academy of Orthopedic Surgeons (AAOS) recommended in 2009 that clinicians should consider antibiotic prophylaxis for all patients with total joint replacement before any invasive procedure that may cause bacteremia. This has aroused confusion and anger among dentists asking for the evidence. The present review deals with different aspects of the rationale for this recommendation giving attention to views both in favor of and against it

Frontiers and Opportunities in Bioenergy Crop Microbiome Research Networks

Researchers from across the four United States Department of Energy Bioenergy Research Centers (BRCs) engaged in a microbiome workshop that focused on identifying challenges and collaboration opportunities to better understand bioenergy-relevant plant–microbe interactions. The virtual workshop included hands-on educational sessions and a keynote address on current best practices in microbiome science and community microbiome standards, as well as breakout sessions aimed at identifying microbiome-related data and measurements that should be prioritized, opportunities for and barriers to integrating plant metabolites to microbiome research, and strategies for more effectively integrating microbiome data and processes into existing models. Based on participant discussion, key findings of the workshop were the need to prioritize scaling data sharing across BRCs and the broader research community and securing collaborative infrastructure in the areas of microbiome-ecosystem modeling and molecular plant–microbe interactions. This workshop review highlights additional main findings from this event, to encourage cross-site and more holistic metaanalyses while promoting wide scientific community engagement across plant microbiome sciences.This article is published as Howe, Adina, Gregory Bonito, Ming-Yi Chou, Melissa A. Cregger, Anna Fedders, John L. Field, Hector Garcia Martin et al. "Frontiers and opportunities in bioenergy crop microbiome research networks." Phytobiomes Journal (2022): PBIOMES-05. DOI: 10.1094/PBIOMES-05-21-0033-MR. Copyright 2022 The American Phytopathological Society. Posted with permission

Plasma drug concentrations and physiological measures in 'dance party' participants

The increasing use of (7) 3,4-methylenedioxymethamphetamine (MDMA) in the setting of large dance parties (‘raves’) and clubs has been the source of some concern, because of potential acute adverse events, and because animal studies suggest that MDMA has the potential to damage brain serotonin (5-HT) neurons. However, it is not yet known whether MDMA, as used in the setting of dance parties, leads to plasma levels of MDMA that are associated with toxicity to 5-HT neurons in animals. The present study sought to address this question. Plasma MDMA concentrations, vital signs, and a variety of blood and urine measures were obtained prior to, and hours after, individuals attended a dance party. After the dance party, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of ‘ecstasy’ and, in some subjects, overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Additional subjects were likely to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications, and suggest that some of these individuals may be at risk for developing MDMA-induced toxicity to brain serotonin neurons.Rodney J Irvine, Michael Keane, Peter Felgate, Una D McCann, Paul D Callaghan and Jason M Whit

Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’): a stressor on the immune system

Drug abuse is a global problem of considerable concern to health. One such health concern stems from the fact that many drugs of abuse have immunosuppressive actions and consequently have the potential to increase susceptibility to infectious disease. This article is focused on the impact of the amphetamine derivative, methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) on immunity. Research conducted over the last 5 years, in both laboratory animals and humans, has demonstrated that MDMA has immunosuppressive actions. Specifically, MDMA suppresses neutrophil phagocytosis, suppresses production of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin (IL)-1β, and increases production of the endogenous immunosuppressive cytokine (IL-10), thereby promoting an immunosuppressive cytokine phenotype. MDMA also suppresses circulating lymphocyte numbers, with CD4(+) T cells being particularly affected, and alters T-cell function as indicated by reduced mitogen-stimulated T-cell proliferation, and a skewing of T-cell cytokine production in a T helper 2 (Th2) direction. For the most part, the aforementioned effects of MDMA are not the result of a direct action of the drug on immune cells, but rather caused by the release of endogenous immunomodulatory substances. Consequently, the physiological mechanisms that are thought to underlie the immunosuppressive effects of MDMA will be discussed. As many of the physiological changes elicited by MDMA closely resemble those induced by acute stress, it is suggested that exposure to MDMA could be regarded as a ‘chemical stressor’ on the immune system. Finally, the potential of MDMA-induced immunosuppression to translate into significant health risks for abusers of the drug will be discussed