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Official websites use. Share sensitive information only on official, secure websites. Correspondence: Leonard L. Dopaminergic mechanisms are thought to mediate the sleep-disrupting effects of stimulant drugs. Morning treatments had no effects on sleep-like parameters. Racemic MDMA decreased general daytime activity during the 1 st hour after injection and increased daytime activity at 3 hours post-treatment. Although afternoon administration of racemic MDMA increased sleep latency, it improved other sleep parameters, decreasing wake time after sleep onset WASO and increasing sleep efficiency for subjects with low baseline sleep efficiency. The stimulant and sleep-disrupting effects of racemic MDMA are likely mediated by dopaminergic and noradrenergic mechanisms, while serotonergic pathways appear to be involved in the sleep-promoting effects of MDMA. Keywords: 3, 4-Methylenedioxymethamphetamine; stereoisomer; sleep; actigraphy; rhesus monkeys. Ecstasy is a commonly used recreational drug, with the most recent edition of the World Drug Report describing nearly Due to those effects, recent studies have investigated the therapeutic utility of racemic MDMA for the treatment of psychiatric disorders such as social anxiety, autism and post-traumatic stress disorder PTSD , with encouraging results Mithoefer et al. However, the broad pharmacological actions of racemic MDMA translate not only into therapeutic efficacy, but also into the generation of adverse effects and abuse liability Hardaway et al. The broad effects of racemic MDMA are mediated mainly by serotonin neurotransmission, as it has high affinity for the serotonin transporter SERT , causing significant increases in extracellular serotonin Berger et al. However, the complexity of effects generated by racemic MDMA seems to be influenced by the differential effects of its stereoisomers. The stimulant nature of racemic MDMA and the putative role of serotonin in sleep Rancillac, have prompted researchers to investigate the effects of racemic MDMA on sleep-wake patterns. Acute racemic MDMA administration has also been shown to increase wakefulness and disrupt objective sleep measures in rodents Balogh et al. In what seems to be the only study to date investigating the effects of acute MDMA on objective sleep measures in humans, a preliminary study with 7 MDMA-using participants showed altered sleep architecture after acute MDMA administration Randall et al. Because sleep architecture in rhesus monkeys strongly resembles that of humans, this is a unique animal model for human sleep Daley et al. Importantly, studies have also shown that the effects of psychostimulant drugs on sleep are also similar in humans and rhesus monkeys Ballard et al. The aim of the present study was to investigate the effects of racemic MDMA on daytime activity and sleep-like parameters evaluated with actigraphy in adult rhesus macaques. Based on the marked serotonergic effects of racemic MDMA, it has been suggested that serotonergic mechanisms mediate chronic MDMA-induced sleep disruption for review, see Parrott, However, studies indicate that the sleep-disrupting effects of stimulant drugs seem to be mediated by dopaminergic mechanisms Andersen et al. Animals were fitted with collars Primate Products prior to the initiation of the studies. Each subject was individually housed in stainless steel home cages and fed Purina monkey chow Ralston Purina, St. Louis, MO , supplemented with fruit and vegetables daily. Water was continuously available in the colony. Environmental enrichment was provided on a regular basis. All subjects had a long history of exposure to psychostimulants Andersen et al. Subjects RZs9, RVm8, and RJl8 had at least 4 years of experience on methamphetamine self-administration prior to this study. Subject RKf9 had a history of occasional every other week psychostimulant exposure during awake fMRI scans for the previous 3 years. Drug doses were calculated and expressed as the salt form. Briefly, the Actiwatch device consisted of an omni-directional sensor that is sensitive to motion recorded as activity counts. The monitors were programmed to record the total piezo-electric voltage generated over the preceding 60 s i. The devices record the intensity, amount, and duration of movement in all 3 planes. Subjects had been adapted to wearing the activity monitors and trained to cooperate with the attachment of the sensor in their collars while seated in primate chairs Primate Products. Nighttime activity data generated the following sleep-like behavior parameters: sleep efficiency i. All parameters were calculated using the Actiware Sleep 3. Sleep measurements were automatically calculated from the underlying activity counts using a temporal smoothing algorithm on the basis that sleeping or wakefulness are continuous behaviors. The Actiware analysis software automatically inferred sleep-like parameters from activity counts during each s epoch by comparing the sum of the activity counts in that epoch and neighboring epochs to a predefined criterion. Actigraphy recording continued for the duration of the treatments. Each subject was administered an intramuscular injection of saline vehicle , racemic MDMA 0. Except for subject RJl8, all other subjects were housed in the same housing room. All experiments were carried out contemporaneously and baseline sleep data were collected during the same week for all animals. Baseline data were combined across a 5 day span of time. Significance was accepted at an alpha of 0. Sleep-like measures are presented as normalized data percentage of baseline. Individual-subject baseline data are presented in Table 1. Correlational analysis showed a negative correlation between baseline sleep efficiency and percent change in sleep efficiency after afternoon treatment with 1. In fact, individual subject data show a dose-dependent increase in sleep efficiency after afternoon racemic MDMA for animals with low, but not high, baseline sleep efficiency Figure 3A. A significant correlation was also observed for sleep efficiency after afternoon treatment with 1. No significant correlations were observed between baseline sleep latency or WASO and percent change in sleep parameters after afternoon treatments with 1. Individual-subject baseline data are presented on Table 1. At the 1 st hour after injection 16h—17h , racemic MDMA dose-dependently decreased general home-cage activity, with 1. While daytime activity returned to baseline levels at the 2 nd hour post-treatment, 1. Analysis of the daytime activity on the days after nighttime MDMA treatments showed no significant differences compared to baseline data not shown. Daytime activity measures are presented as normalized data percentage of baseline. Morning treatment with either compound had no effects on sleep-like parameters. Treatment with racemic MDMA decreased general daytime activity during the 1 st hour after injection, while showing daytime stimulant effects at 3 hours post-treatment. In agreement with the daytime stimulant effects, afternoon treatment with racemic MDMA induced a marked dose-dependent increase in sleep latency in all subjects, with no significant differences on sleep efficiency. The biphasic effects of racemic MDMA on daytime activity observed in the present study had been previously reported in rhesus monkeys. Crean and colleagues Crean et al. Similarly, a recent study from our group has shown decreased general daytime activity during the 1 st hour following racemic MDMA administration in squirrel monkeys Pitts et al. However, the present findings suggest that, contrary to what is observed for other psychostimulant drugs such as amphetamine Murnane et al. Racemic MDMA shows a lower dopamine to serotonin release profile compared to other psychostimulant compounds Rothman et al. Consistent with the daytime stimulant effects emerging at 3 hours post-treatment, afternoon treatment with racemic MDMA induced a marked dose-dependent increase in sleep latency. The present findings are in agreement with previous studies showing that increased sleep latency is the main sleep-related effect of acute racemic MDMA administration. A preliminary study in humans has also reported reduced SWS and REM sleep time after acute MDMA administration, with shortened sleep primarily due to increased sleep latency, when participants were given an 8-hour sleep opportunity Randall et al. Both in the studies with rodents Balogh et al. Similar effects have been previously reported for other psychostimulant drugs, such as amphetamine Murnane et al. Importantly, in the study by Crean and colleagues Crean et al. Although the authors show that this effect was not coupled to MDMA-induced changes in daytime activity Crean et al. Changes in core body temperature have a major influence on sleep regulation and are known to affect the ability to initiate sleep Romeijn et al. Because other psychostimulant drugs, such as methamphetamine, also induce hyperthermia in rhesus monkeys Crean et al. Although racemic MDMA and other amphetamine-type drugs exert similar effects on sleep latency, those drugs seem to exert distinct effects on other sleep parameters. In our previous studies, amphetamine and methamphetamine administration also impaired sleep by decreasing sleep efficiency and increasing sleep fragmentation Murnane et al. While MDMA had no significant effects on sleep fragmentation data not shown , it significantly decreased WASO, also increasing sleep efficiency in animals with low baseline sleep efficiency. As previously mentioned, one of the main differences between MDMA and other psychostimulant drugs is that racemic MDMA acts predominantly as a serotonin releaser, showing a low dopamine to serotonin release profile Rothman et al. Thus, we propose that the stimulant effects of MDMA on daytime activity are a consequence of the dopamine-releasing effects of racemic MDMA, and that increased dopamine levels impair sleep onset when racemic MDMA is given close to bedtime afternoon treatments. However, racemic MDMA-induced serotonin release would also activate sleep-promoting serotonergic pathways and improve sleep measures after sleep onset and throughout the night. Because racemic MDMA also potentiates the activity of other neurotransmitter systems, it cannot be ruled out that other neural pathways might also be modulating its effects on daytime activity and sleep. NE is involved in the ascending arousal system, and high extracellular NE levels enhance neurotransmission along wake-promoting pathways Mitchell and Weinshenker, Thus, in addition to changes in dopamine and serotonin neurotransmission, increased NE levels could also account for the increased sleep latency observed following racemic MDMA administration. Regarding the effects of serotonin on sleep, previous studies in humans have shown that acute treatment with the serotonin releaser fenfluramine and the serotonin reuptake inhibitor citalopram had no effects on sleep efficiency, sleep latency or wake time after sleep onset in humans Myers et al. However, changes in sleep architecture were observed after the administration of both compounds, including decreased percentage of time spent in slow wave sleep and changes on sleep power spectral parameters, with citalopram also decreasing percentage of time spent in REM sleep Myers et al. The same study by Neckelmann and colleagues also showed that the effects of chronic treatment with citalopram on sleep parameters were different from those of acute citalopram administration, with more prominent changes in sleep architecture after chronic treatment. Several studies have investigated the role of serotonin in the regulation of sleep-wake cycles, and yet the serotonergic pathways regulating sleep remain incompletely understood. Studies suggest that serotonin can have both an inhibitory and an excitatory effect in the ventrolateral preoptic nucleus VLPO , the main sleep center in the brain, depending on the type of neuron that is being targeted Rancillac, In fact, we have previously shown that antagonism of 5-HT 2A receptors as well as activation of 5-HT 2C receptors decrease the sleep-disrupting effects of amphetamine-type stimulants in rhesus monkeys Murnane et al. Thus, the sleep-promoting effects of racemic MDMA appear to be regulated by serotonergic pathways. The half-life of intravenous MDMA in rhesus monkeys is approximately 90 min, reaching maximum plasma concentration at 5 min after injection Banks et al. Accordingly, serotonin and prolactin levels induced by racemic MDMA return to baseline levels 90 min post injection Murnane et al. Its metabolites, on the other hand, are still detected in the plasma for at least 4 hours after drug administration Banks et al. However, studies in rodents Fitzgerald et al. Due to its mood-enhancing and prosocial effects, recent studies have investigated the therapeutic utility of racemic MDMA for the treatment of psychiatric disorders such as social anxiety, autism and post-traumatic stress disorder PTSD , with encouraging results Mithoefer et al. The broad pharmacological actions of racemic MDMA, however, translate not only into therapeutic efficacy, but also into the generation of adverse effects and abuse liability. Although it has never been studied in humans, racemic MDMA seems to have significant abuse potential Hardaway et al. In addition, in the present study afternoon treatment with racemic MDMA induced stimulant effects and delayed sleep onset. Thus, the balance between benefit and risk is one of the major challenges for the clinical use of racemic MDMA. The funding sources had no other role other than financial support. All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript for publication. As a library, NLM provides access to scientific literature. Exp Clin Psychopharmacol. Published in final edited form as: Exp Clin Psychopharmacol. Find articles by Hannah Shields. Find articles by Melis Odabas-Geldiay. Find articles by Barbara O Rothbaum. Find articles by Monica L Andersen. Find articles by Leonard L Howell. Issue date Aug. PMC Copyright notice. The publisher's version of this article is available at Exp Clin Psychopharmacol. Individual-subject baseline daytime activity and sleep-like parameters. Open in a new tab. Disclosures All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript for publication. The authors declare no conflicts of interest. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
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Background: Post-traumatic stress disorder PTSD is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. Methylone is currently in clinical development for the treatment of PTSD. Preclinical studies show rapid, robust and long-lasting antidepressant-like and anxiolytic effects. The mechanism of action underlying these effects is not yet fully understood. This study investigated the downstream gene expression changes and signaling pathways affected by methylone in key brain areas linked to PTSD and MDD. It also sought to determine whether neuroplasticity-related genes were involved. We confirmed changes in gene expression using immunohistochemistry. RNA-seq results revealed significant regulation of myelin-related genes in the amygdala, confirmed by immunohistochemistry. In the frontal cortex, methylone significantly upregulated genes implicated in neuroplasticity. Conclusion: Results suggest that 1 methylone is a rapid-acting neuroplastogen that affects key brain substrates for PTSD and MDD and that 2 methylone appears to exhibit higher specificity and fewer off-target effects than MDMA. Together, these results are consistent with the reported clinical experiences of methylone and MDMA and bolster the potential use of methylone in the treatment of PTSD and, potentially, other neuropsychiatric disorders. Post-traumatic stress disorder PTSD is a debilitating disorder characterized by intrusive flashbacks of a traumatic event, heightened arousal, mood changes, and a high rate of comorbidity with other CNS disorders including major depression MDD. PTSD has an estimated lifetime prevalence of 6. However, the treatment requires extensive concomitant psychotherapy and integrations sessions, its effects are reduced by prior SSRI exposure, and some patients report feeling anxious, fatigued or depressed for days after MDMA use. Methylone has been well-tolerated in several human studies Poyatos et al. Recent data from an open-label study of methylone in 14 PTSD patients showed a Importantly, methylone offers several key advantages over MDMA, including a reduced need for specialized concomitant psychotherapy and the potential for coadministration with SSRIs Feduccia et al. We have reported that methylone has rapid-acting, robust and long-lasting antidepressant-like and anxiolytic activity in rodents Warner-Schmidt et al. Results were not due to any locomotor stimulating effects, and anxiolytic effects in the Open Field Test were observed on the same timescale. Methylone also showed a rapid and robust improvement in fear extinction in a mouse model of PTSD which was also not attributed to locomotor effects or diminished by previous SSRI exposure Yu et al. In addition, methylone has shown significant antidepressant-like effects in stress-induced tests like learned helplessness, social defeat, and the sucrose preference Li et al. The mechanism underlying the lasting behavioral effects of methylone is not yet understood. Antidepressants exert their lasting effects at least in part by increasing neuroplasticity in key brain areas, including the amygdala and prefrontal cortex. For example, chronic daily dosing with SSRIs rescue dendritic spine loss in the prefrontal cortex caused by stress Bessa et al. Rapid-acting antidepressants also induce neuroplastic changes, but on a shorter timescale Licznerski and Duman, Various genes and pathways responsible for neuroplastic changes have been described and include neurotrophic factors like brain-derived neurotrophic factor BDNF Yang et al. Therefore, analysis of drug-induced RNA expression can serve as a useful screening tool to probe the neuroplastic effects of novel compounds. This study aims to understand the molecular mechanisms underlying the long-term behavioral effects of methylone and MDMA, and how differences in their pharmacokinetic properties may account for differences their acute effects. To do so, the pharmacokinetic activities of methylone and MDMA at monoamine transporters and GPCRs and changes in RNA expression in key limbic brain areas were examined to further elucidate potentially clinically important pharmacokinetic and neuroplastic changes. Because these compounds are structurally similar and induce comparable therapeutic effects, we hypothesize that genes changed by both methylone and MDMA reflect therapeutic targets, such as neuroplasticity-related genes, in the amygdala and frontal cortex. Lastly, due to their different acute effects, we hypothesize that methylone and MDMA will also lead to drug-specific alterations in gene expression profiles compared with each other. Male Sprague Dawley rats Envigo were used for binding, uptake and release assays were kept at Gifford Bioscience, Ltd. Birmingham, UK. All studies were performed at Gifford Bioscience, Ltd. Birmingham, UK according to standard protocols. On the day of the assay, the membrane preparation was thawed and the pellet resuspended in final assay buffer. For each concentration of drug, non-specific binding was subtracted from total binding to give specific binding. K i was subsequently calculated using the Cheng-Prusoff equation. Brains were dissected and tissue was added to sucrose buffer 0. The pellet was resuspended in fresh assay buffer. The incubation was stopped by vacuum filtration onto presoaked 0. For each concentration of drug, non-specific uptake was subtracted from total uptake to give specific uptake. Test compounds and synaptosomes were prepared as described for uptake inhibition assays. Oxygenated Krebs buffer was perfused through the chambers at a rate of 1. Trapped air bubbles were removed from the filters prior to collecting fractions to ensure an even flow over the synaptosomal bed. Following collection, an aliquot of 0. Once all fractions had been collected, the filters holding the synaptosomes were removed, dried under a stream of warm air. Scintillation cocktail was added, and the filters counted to determine residual radioactivity. Drug-evoked release of neurotransmitter was calculated by subtracting the average of the two basal fractions collected prior to the drug addition , from the four fractions collected in the presence of drug. The drug-evoked release was then expressed as a percentage of the basal release. Potassium-evoked release was calculated by subtracting the average of two fractions collected prior to the addition of high KCl buffer from that in the two fractions following addition of high KCl buffer. Potassium-stimulated release was calculated as a percentage of basal release. The drug evoked release as a function of drug concentration plotted and the data fitted. All calculations were performed with MOE Docking was used to examine potential ligand binding to receptors with experimentally determined structures. The process to prepare the crystallographic protein structures for modeling work as well as preparing the ligands for docking is described below. In MOE, the QuickPrep procedure was used to standardize and minimize the protein structure subject to tethers on the receptor to relax any strain in the structure while keeping it close to the experimental coordinates. This procedure also determines the ionization state of both protein sidechains and the ligand. After protein preparation, structures were superposed into a common reference frame to compare the binding modes of different ligands. This was followed by conformational generation using the stochastic search method to ensure complex ring systems were adequately sampled. All generated conformations were used as input for docking. Frontal cortex and amygdala were rapidly dissected and immediately frozen. RNA samples were quantified using Qubit 2. First strand and second strand cDNA were subsequently synthesized. The sequencing libraries were clustered on 5 lanes of a flowcell. Image analysis and base calling were conducted by the Control software. Raw sequence data. One mismatch was allowed for index sequence identification. After investigating the quality of the raw data, sequence reads were trimmed to remove possible adapter sequences and nucleotides with poor quality. The STAR aligner is a splice aligner that detects splice junctions and incorporates them to help align the entire read sequences. BAM files were generated as a result of this step. Unique gene hit counts were calculated by using feature Counts from the Subread package v. Only unique reads that fell within exon regions were counted. Pathway analysis was performed on selected gene lists based on a statistical cutoff 0. All analyses were completed using Graphpad Prism software version 9. Figure 1. Methylone and MDMA release monoamines. The greatest activity detected was for 5HT5A Figure 2. Together these data suggest that methylone has no off-target activity at GPCRs whereas MDMA shows some activity at serotonin receptors, consistent with previous reports Luethi et al. The diagram Figure 3C shows low energy conformations generated for methylone blue or MDMA purple superimposed on the bicyclic ring system. The ketone in methylone leads to very different shapes with little to no overlap with MDMA. Given subtle differences in receptor binding pocket topography across substrates, the shape difference between MDMA and methylone could lead to very different binding profiles. In silico modeling based on the known structures shows that at the 5HT2A receptor, MDMA fits the docking site well but methylone does not fit due to shape differences that cause strain energy Figures 3D , E. However, due to the very different conformation of methylone, the docking algorithm cannot fit methylone into the binding pocket without generating steric clashes indicated by the orange disks Figure 3F. The results of the docking study are in alignment with the results from the GPCR screen and show that conformational differences between methylone and MDMA may be a contributing factor to the differences in binding to off-target receptors. Figure 3. Orange disks indicate steric clashes. Blue cylinders and dashed lines illustrate hydrogen bonds. Figure 4. Methylone- and MDMA-induced gene expression changes in the amygdala. Light gray dots represent genes that were not significantly changed by either treatment. C The number of significantly down- or upregulated genes was quantified. D An illustration of our hypothesis that genes regulated by both methylone and MDMA are linked to potential therapeutic activity and that genes regulated by methylone or MDMA only are drug-specific and reflect potential off-target effects. The number of genes significantly up- or downregulated by methylone or MDMA compared to vehicle were quantified. Significantly more gene expression changes were induced by MDMA in amygdala than methylone compared to vehicle controls Figure 4C. Therefore, we hypothesized that genes commonly changed by both methylone and MDMA reflected those linked to therapeutic activity while drug-specific transcriptional changes underlied drug-specific and potentially off-target effects Figure 4D. Quantification of the number of significantly regulated genes revealed that nearly all the genes significantly regulated by methylone were also regulated by MDMA. To classify the list of MDMA-regulated genes and associate them with a particular phenotype, pathway or function, functional enrichment analysis was performed on the downregulated Figure 5A and upregulated genes Figure 5B in MDMA-treated animals. Figure 5. Functional enrichment analysis of genes regulated only by MDMA in the amygdala. All enrichment terms shown were highly statistically significant. Methylone treatment did not significantly upregulate many genes in the amygdala Figure 4E , so functional enrichment analysis focused only on downregulated genes by methylone Figure 6A or MDMA Figure 6B. Figure 6. Myelin genes are downregulated in the amygdala after treatment with methylone or MDMA. Figure 7. Rapid induction of myelin plasticity by methylone and MDMA and the amygdala. Areas in black boxes are magnified below. Our results also revealed that the most highly significantly downregulated gene by methylone was Ankyrin Repeat and Kinase Domain Containing 1 Ankk1 , which regulates dopamine synthesis and has been associated with PTSD susceptibility Niu et al. The top 10 most significant enrichment terms upregulated by methylone included almost exclusively terms linked to synaptic plasticity, cytogenesis and survival, and neurotrophin signaling e. MDMA also regulated neuroplasticity genes Figure 8B , but the top 10 enriched terms differed slightly from those of methylone. Orexin receptor pathway and protein folding were also top MDMA enrichment terms in the frontal cortex as observed in the amygdala Figure 6B , 8D. Together, these results point to changes in synaptic plasticity as a key step in the mechanisms of action of methylone and MDMA and to the specificity of methylone compared with MDMA. Figure 8. Gene changes in the frontal cortex suggest rapid-acting neuroplasticity. Red circles highlight neuroplasticity-related genes discussed in the results section. Effects were compared with MDMA to identify similarities and differences between the two compounds that might underlie on- and off-target effects, respectively. Overall, the results from the RNA-seq analysis demonstrated that methylone exhibits a narrower impact on neuroplastic pathways, indicating a more specific mechanism of action compared with MDMA. This discrepancy could be due to methodological differences. For example, our study was performed in rat brain synaptosomes and the published studies utilized transfected HEK cells. However, recent results using fiber photometry to measure neurotransmitter release in vivo are consistent with our results, showing that methylone raises levels of both 5HT and NE in the prefrontal cortex to the same extent as MDMA Yu et al. Since dopamine release is involved in impulsivity, emotional sensitivity, and addictive behaviors Pine et al. In addition to its effects on monoamine transporters, MDMA has been reported to bind to 5HT, adrenergic and other receptors Luethi et al. Differences in the structures of methylone or MDMA could contribute to the observed differences in binding. While the similar overall chemical structures of MDMA and methylone might suggest similar binding characteristics, several important discrepancies can lead to major differences in potential binding to a given receptor. First, methylone contains a ketone carbonyl giving it a hydrogen bond acceptor that is not present in MDMA. This gives important physiochemical differences between the two molecules. For example, methylone has a more polar surface area. Second, the carbonyl in methylone causes significant conformational differences compared with MDMA. Specifically, it is a difference in the torsional energy profile for a ketone to aromatic bond compared to a Csp3 to aromatic bond for MDMA. Since the hallucinogenic activity of classic psychedelics like psilocybin or LSD have been linked to 5HT2A receptor activation Lopez-Gimenez and Gonzalez-Maeso, , our findings provide molecular evidence that support the observation that methylone is non-hallucinogenic in animals and humans Poyatos et al. Although MDMA is not a classic hallucinogen, hallucinogenic activity has been reported in some studies Holze et al. Our results suggest that methylone would have less effect on 5HT2C-mediated behavior. The amygdala is a key neural substrate for emotional learning whose activity is dysregulated in neuropsychiatric disorders including PTSD, MDD and anxiety Price, ; Ressler, The amygdala is also a part of neural circuit that has been well-characterized for its involvement in fear conditioning and extinction Fenster et al. In contrast, genes and pathways regulated by either drug alone might reflect off-target effects. In the amygdala, over a fifth of the transcripts downregulated by both methylone and MDMA encoded myelin-related genes. Stress and antidepressants induce structural and functional changes to brain circuitry i. More recent work shows that adult myelin plasticity is required for proper synaptogenesis, circuit function and learning. Myelin and the oligodendrocytes that produce it play key roles in stress, behavior, and experience-dependent plasticity Monje, ; Pan et al. Activity dependent changes in myelin, including regulation of oligodendrocytes by BDNF and neurotransmitters, has also been described Monje, ; Xin and Chan, Increased myelination in the prefrontal cortex correlates with depression Liu et al. Most notably, a recent study in humans and animals found that increased myelin in the amygdala was associated with PTSD susceptibility and correlated with fear conditioning in animals Long et al. Our results show that methylone and MDMA rapidly reduce myelin in the amygdala, suggesting a mechanism for the rapid-acting effects of these drugs. We speculate that the rapid effect on myelin is a neuroplastic event that makes the aberrant connections that underlie the persistent fear response in PTSD more malleable and facilitates the rewiring of the neural circuit. Genes related to protein folding and degradation, including a number of heat shock proteins HSPs were significantly regulated by MDMA and not methylone. HSPs are induced by a variety of environmental stressors including infection and inflammation, but their upregulation might also indicate a mechanism of cytoprotection Santoro, More work needs to be done understand the role of these factors in the effects of MDMA. Orexins are neuropeptides produced in the hypothalamus that have been described to serve several functions depending on the brain area involved. Typically described for their role in wakefulness or response to external stimuli, orexins have been implicated in functions including stress, arousal, vigilance, feeding, reward processing, and drug addiction Marcus et al. MDMA has been reported to increase energy, reduce appetite and have some potential for addiction, all of which could be mediated by orexins Baylen and Rosenberg, Cytokine signaling was also regulated by MDMA. MDMA has been described previously as an immune system stressor Connor, Cytokines can mediate depression and anxiety behaviors Hu et al. Notably, no such changes were observed with methylone treatment. Overall, the effects of methylone on gene expression were more variable between animals than MDMA, which could be due to experimental or biological variability or differences in their neurotransmitter profiles e. However, MDMA regulated many more genes, pathways and functions than methylone. These results offer a molecular explanation for the differences between acute effects of methylone and MDMA. The prefrontal cortex shares strong connectivity with the amygdala and has been described as a critical substrate for fear conditioning and PTSD Alexandra Kredlow et al. It is also a substrate of antidepressant effects on neuroplasticity Moda-Sava et al. Antidepressants have been well-studied for their effects on neuroplasticity, synaptic remodeling Moda-Sava et al. However, it takes weeks of daily treatment with antidepressants to induce these neuroplastic changes in the brain, correlating with the observed therapeutic delay. Ketamine, a rapid-acting antidepressant, has been shown to induce a sustained increased in neurotrophins like BDNF within hours also correlating with its therapeutic effects Deyama and Duman, Infusions of BDNF into the prefrontal cortex reduce conditioned fear, even in the absence of extinction training Peters et al. In addition to BDNF, a variety of other genes linked to neuroplasticity were among the most significantly upregulated genes by methylone, including Vgf, Camk1g, Selenom, Nfil3, Psrc1, and Nptx2. Vgf is a neuropeptide that has been linked to the antidepressant-like effects of exercise Hunsberger et al. Camk1g is a neuron-specific glucocorticoid-regulated transcription factor whose activity in the amygdala underlies anxiety-related and fear conditioning behavior Piechota et al. Selenom is reported to affect synaptic plasticity and cognitive function Lin et al. Nfil3 is a transcription factor that regulates expression of synaptic plasticity genes and is implicated in the regulation of inhibitory long-term potentiation iLTP and depression iLTD Chapman et al. Psrc1 is a microtubule associated protein that promotes cell growth by stimulating the beta-catenin pathway Hsieh et al. Nptx1 is a member of a family of proteins that play a crucial role in homeostatic synaptic plasticity by recruiting post-synaptic receptors into synapses. Nptx1 specifically regulates excitatory synaptic plasticity and is essential for the maintenance of LTP Chapman et al. These genes were also regulated by MDMA. Together, these results point to rapid and robust changes in gene expression related to rapid-acting neuroplasticity. Given the molecular evidence for rapid-acting neuroplasticity following methylone and MDMA administration, future studies will explore the effects of methylone and MDMA on structural and functional neuroplasticity and neurocircuitry that underlie neuropsychiatric disorders. Together, the results of the current study suggest that 1 methylone is a rapid-acting neuroplastogen, rapidly regulating the expression of key synaptic plasticity genes and neurotrophins in brain areas linked to PTSD, MDD and anxiety and 2 overlapping effects of methylone and MDMA are observed and may underlie their common therapeutic effects, but 3 Methylone shows increased specificity as MDMA regulates additional gene expression changes with distinct functional classification, that may be tied to off-target activity. The study was conducted in accordance with the local legislation and institutional requirements. BK is a co-founder, scientific advisor, and has equity in Transcend Therapeutics. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Alexandra Kredlow, M. Prefrontal cortex, amygdala, and threat processing: implications for PTSD. Neuropsychopharmacology 47, — Aston-Jones, G. Brain structures and receptors involved in alertness. Sleep Med. Brain Res. Averill, L. A case series providing clinical evidence that Methylone produces rapid and robust improvements in major depressive disorder. Ann Clin Case Rep. Crossref Full Text Google Scholar. Bauer, C. Role of 5-HT 2 C receptors in effects of monoamine releasers on intracranial self-stimulation in rats. Psychopharmacology , — Bayer, K. CaM kinase: still inspiring at Neuron , — Baylen, C. Addiction , — Bessa, J. 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Psychiatry 5:e Yu, A. Norepinephrine blocks psychedelic-like effects of entactogens and psilocybin in mice. Zhou, Y. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA. Scott Rowland 2 Eric F. Schmidt 3 Benjamin Kelmendi 4,5. Introduction Post-traumatic stress disorder PTSD is a debilitating disorder characterized by intrusive flashbacks of a traumatic event, heightened arousal, mood changes, and a high rate of comorbidity with other CNS disorders including major depression MDD. Binding, uptake and release assays All studies were performed at Gifford Bioscience, Ltd. Release assay Test compounds and synaptosomes were prepared as described for uptake inhibition assays. Docking All calculations were performed with MOE Protein preparation In MOE, the QuickPrep procedure was used to standardize and minimize the protein structure subject to tethers on the receptor to relax any strain in the structure while keeping it close to the experimental coordinates. Library preparation with polyA selection and illumina sequencing RNA samples were quantified using Qubit 2. Data analysis After investigating the quality of the raw data, sequence reads were trimmed to remove possible adapter sequences and nucleotides with poor quality. Pathway analysis Pathway analysis was performed on selected gene lists based on a statistical cutoff 0.
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