Ecstasy (MDMA) Vrsar
Ecstasy (MDMA) Vrsar______________
Наши контакты (Telegram):
>>>НАПИСАТЬ ОПЕРАТОРУ В ТЕЛЕГРАМ (ЖМИ СЮДА)<<<
_______________
ВНИМАНИЕ !!! ВАЖНО !!!
В Телеграм переходить только по ССЫЛКЕ что ВЫШЕ, в поиске НАС НЕТ там только фейки !!!
Чтобы телеграм открылся он у вас должен быть установлен!
_______________
MDMA (Ecstasy) Addiction: Signs Of Abuse And Treatment Options
Nevertheless, the roles of specific positions of the aromatic ring of MDMA associated with the modulation of typical entactogenic effects, using analogs derived from the MDMA template, are still not fully understood. Among many possibilities, aromatic halogenation of the phenylalkylamine moiety may favor distribution to the brain due to increased lipophilicity, and sometimes renders psychotropic substances of high affinity for their molecular targets and high potency in humans. Besides, its effects on platelet aggregation were performed in platelet enriched human plasma using collagen as aggregation inductor. Second, as platelets are considered an appropriate peripheral model for estimating central serotonin availability, the functional effects of 2-Br-4,5-MDMA and MDMA on ATP release during human platelet aggregation were evaluated. Subsequent in vivo evaluation in rats at three dose levels showed that 2-Br-4,5-MDMA lacks all key MDMA-like behavioral responses in rats, including hyperlocomotion, enhanced active avoidance conditioning responses and increased social interaction. Due to these properties, evidence has accumulated regarding the potential applications of MDMA in psychotherapy Parrott, ; Mithoefer et al. Figure 1. Reference values of K i for serotonin and citalopram were and 0. As the basis of MDMA-like activity deserves to be explored for therapeutic purposes, efforts to develop MDMA analogs included mainly classical derivatives Shulgin and Shulgin, and more recently synthetic cathinones Morris, and benzofurans Liechti, Interestingly, it was further found that the ring-methylated MDA derivatives 1- 2-methyl-3,4-methylenedioxyphenyl - and 1- 3-methyl-4,5-methylenedioxyphenyl aminopropane are not only fairly potent 5-HT releasers in rats but also substitute, at low doses, for the entactogen-like MBDB and MMAI in the drug discrimination paradigm, whereas the positional isomer 1- 2-methyl-4,5-methylenedioxyphenyl aminopropane is four times less potent than MMAI and only substitutes partially for MBDB Parker et al. This evidence suggests that rational modifications of the benzene ring of MDMA can lead to potentially new analogs sharing some of the distinctive MDMA-like effects. As bromine can be considered as bio-isosteric to the methyl group, one should expect that appropriately brominated analogs of MDMA could exhibit similar MDMA-like properties. Nevertheless, and despite its relevance, the pharmacological characterization of the effects of aromatic halogenation on the mode of binding at SERT referred to MDMA remains fragmentary and incomplete. This notion is supported by some members of the heterogenous group of psychotropic phenylalkylamines, including MDMA. Indeed, aromatic halogenation of structurally-related phenylalkylamine molecules can render hallucinogens of high potency in vivo Barfknecht and Nichols, ; Shulgin and Shulgin, and high affinity for their corresponding molecular targets e. Regardless of the fact that the latter evidence should not necessarily extend to monoamine transporters, one could expect that aromatic bromination might induce similar effects on the mode of binding of MDMA. Consequently, we hypothesize that bromine substitution may increase the pharmacological features of MDMA, including SERT affinity, the ability to act as a SERT substrate and the distinctive behavioral effects already known for Ecstasy. In addition, the effects on platelet aggregation were performed in platelet enriched human plasma using collagen as aggregation inductor. As platelets also possess a high SERT density, they are considered a suitable peripheral model to estimate central serotonin availability from the periphery and the amount of ATP released during platelet aggregation may be used as an indirect estimate of the activation level of SERT Maurer-Spurej, ; Mercado and Kilic, Both drugs were tested as racemic mixtures, considering that this is the form commonly used in clinical and recreational settings. All reagents and solvents were commercially available from Sigma-Aldrich St. Coupling constants J are given in Hz. After purification by crystallization, the reaction product was reduced to the amine with LiAlH 4. Then, 1. The reaction was held at room temperature for 6 h. All volatile components were removed under vacuum affording a red colored oil, that was treated without purification with LiAlH 4 1. The reaction was kept at room temperature for 24 h. HBr Figure 1A , which was obtained as white crystals 1. It was then resuspended in 10 mL buffer A to yield a final protein concentration of about 0. Both platelet aggregation and ATP release from platelets were simultaneously measured using a lumi-aggregometer Chrono-Log, United States. Each sample was stirred at rpm for 1 min before testing. Samples were further pretreated in the presence of different concentrations The resulting aggregations were measured as changes of light transmission that were recorded for 8 min. The extent of platelet aggregation was expressed as percentage of light transmission in a platelet-free medium. A total of 80 adult male Sprague-Dawley rats, weighing — g, were purchased from the rearing facility of the Pontifical Catholic University of Chile, and housed eight per cage in a temperature-controlled vivarium under a h light-dark cycle lights on from to h , with free access to standard rodent pellet diet and tap water. Behavioral observations took place in a sound-proof room at the same time of day to reduce the confounding influence of diurnal variation on spontaneous behavior. Each animal was tested only once, and the minimum number of animals and duration of observations required to obtain consistent data were employed. Experimental protocols were conducted in accordance with international standards of animal welfare and following the Guide for Care and Use of Laboratory Animals, National Research Council, United States, and were approved by the Bioethics Committee of the University of Santiago de Chile. Each drug was freshly dissolved in saline 0. Each experimental group consisted of 6—8 animals. Saline was used as control treatment. The floor of the cage was an activity platform Lafayette Instrument Co. Locomotor activity was also recorded with an infrared photocell activity monitor Columbus Instruments, United States , provided with an array of 15 infrared photocells spaced 1 in. Total motility and locomotor activity were monitored every 5 min during a 30 min period. Simultaneously, the number of rearings, head shakes and the time in seconds spent in grooming behavior were manually recorded. Global spontaneous motor activity measures the total motor activity of the animal, including grooming, head shakes, rearing and locomotion. In contrast, locomotor behavior measures the horizontal displacement of the animal only. All the observations were recorded in real time using a digital camera connected to a PC, and video sequences were used for later reanalysis when necessary. This test has been widely validated to measure anxiety in rodents Pellow and File, The maze was elevated 70 cm above the floor. Each animal was placed at the center of the maze, facing one of the closed arms. During a test period of 5 min, an observer recorded: a the number of open-arm entries; b the number of closed-arm entries; c the time spent in open arms; and d the time spent in closed arms. Arm entries were counted when the animal placed all four paws in an arm. Because illumination seems to play a crucial role in the plus-maze behavior of rats Mora et al. The results were expressed as percentages of open-arm entries and of time spent in open arms, with regard to the total number of arm entries and the total time spent in both open and closed arms, respectively. Since, in this test, anxiety is reflected in the unconditioned aversion to heights and open spaces, the percentage of entries and time spent in open arms provide measures of fear-induced inhibition of exploratory activity. This ratio is increased by anxiolytic and reduced by anxiogenic compounds Pellow et al. Each rat was individually placed into a two-way shuttle box Lafayette Instrument Co. Electric shocks were delivered to the grid floor by a master shock supply Lafayette Instrument Co. The rats were trained over 50 trials, after a 5 min period of habituation. Each trial consisted of the presentation of a tone that after 5 s was overlapped with a 0. Between trials, the animal was allowed to rest for at least 15 s. A conditioned avoidance response CAR was defined as a crossing to the opposite chamber within the first 5 s tone alone. If the rat did not escape by crossing to the opposite chamber during the foot-shock, this was considered as an escape failure EF. To evaluate social interaction, a modification of the method described by File was employed. A pair of Sprague Dawley rats — g coming from different cages i. Rat pairs injected with saline i. To do this, the time in seconds spent on diverse behaviors related to social interaction approach and remaining side-by-side with the partner, general and anogenital sniffing of the partner and the number of rearings and times lying belly down were scored independently for the two rats by two experienced persons. The test was conducted under low artificial illumination conditions approximately 10 lux , and all observations were recorded in real time using a digital camera connected to a PC. For the effects on platelet aggregation, ATP release from platelets and rat behavior, data were analyzed by two-way ANOVA followed by the Dunnett intragroup comparisons against saline control or the Bonferroni intergroup comparisons at similar concentrations or doses multiple comparison post hoc tests. A probability level of 0. Therefore, K i. Figure 2. Significance symbols arising from post hoc tests indicate either intragroup differences after Figure 3. Saline Sal was used as control. Behaviors were scored during 30 min, starting 30 min after drug or saline administration. In contrast, 2-Br-4,5-MDMA was unable to increase plus-maze open arms exploration at any of the doses used. On the other hand, the total number of entries into closed and open arms were not statistically different between 2Br-4,5-MDMA and MDMA, both being indistinguishable from controls data not shown. Figure 4. These results indicate that bromination of MDMA impairs the ability of the drug to improve acquisition in rats subjected to an active avoidance conditioning paradigm, together with producing an increase in escape failures. Figure 5. Thus, the foregoing experimental series indicate that 2-Br-4,5-MDMA is almost unable to promote either the lying next to the partner response nor the lying belly down behavior, and did not significantly alter the other indexes of social interaction evaluated. Figure 6. Saline was used as control. The central aim of the present work was to determine the affinity and activity at SERT of the brominated ecstasy analog 2-Br-4,5-MDMA, as well as its effects on the distinctive acute behavioral hallmarks of MDMA in classical spontaneous psychomotor models and social interaction in rats. In contrast, for other behavioral responses that have been described as non-MDMA distinctive hallmarks e. Moreover, because these effects were reported to be different compared to those expected for structurally related psychedelics Nichols and Glennon, , it was proposed that the unique behavioral effects of MDMA might be mediated through its actions at SERT Rudnick and Wall, Indeed, more recent evidence further elaborated that the acute psychotropic effects elicited by MDMA could be explained by means of a presynaptic mechanism that involves a reversal of the direction of transport of 5-HT through SERT elicited by the drug acting as a substrate Sitte and Freissmuth, ; Dunlap et al. Further, a mechanistic evaluation of the inhibition effects induced is consistent with the notion that 2-Br-4,5-MDMA might inhibit platelet aggregation by blocking the platelet serotonin resorption processes only, as also seems to be the case for the partial inhibition induced by MDMA data not shown. A similar effect has already been reported for the SERT blocker citalopram at the same concentration using a similar experimental approach Tseng et al. Nevertheless, considering the large differences among affinities at SERT, one may suggest that 2-Br-4,5-MDMA is a more potent blocker of serotonin influx than citalopram. The results obtained suggest that aromatic bromination at C 2 might modify the pharmacological profile of MDMA, favoring the establishment of blocking-like interactions at SERT that may account for the inhibition of platelet aggregation observed. In addition, although alterations in ATP release in the platelet model should be considered as an indirect measurement of possible differential functional activities at SERT Tseng et al. Indeed, aside from the concentration range considered, the inhibition of ATP release elicited by 2-Br-4,5-MDMA and citalopram reached almost the same maximum Tseng et al. Despite the latter, as ATP release inhibition should be considered as an indirect evidence of alterations in SERT functionality, experiments evaluating 5-HT release are required to characterize these effects further. Until recently, it was proposed that SERT should possess different binding sites for substrates and inhibitors Gabrielsen et al. Nevertheless, the X-ray structure of the human SERT bound to citalopram and paroxetine published recently differs in some extent from this model Coleman et al. Indeed, the structure shows two binding sites: S1 thought to be the common binding site for blockers and S2 allosteric or vestibular binding site , but crystallographic data indicate that citalopram may bind to both binding sites as part of a complex, stereospecific interaction process that accounts for its antidepressive effects that may be mechanistically different from other selective serotonin reuptake inhibitors such as paroxetine Topiol et al. On the other hand, because citalopram binds at both S1 and S2, an interesting question to address might be if this mode of binding is shared by 2-Br-4,5-MDMA. In this regard, an interesting possibility associated with the preference for S2 might be the occurrence of halogen bonding Zhou et al. Further research is needed to consider these possibilities. In order to address the complexity of the relationship between a presynaptic mechanism and its behavioral implications, most efforts have been focused on the elucidation of the molecular mechanism associated with transport reversal, mainly at human SERT. This critical event has been proposed to be responsible for the psychotropic effects elicited not only by MDMA at SERT but also by structurally related stimulants such as amphetamine and methamphetamine at the dopamine transporter Sitte and Freissmuth, , Moreover, a substrate-mediated neurotransmitter efflux is considered to be a distinctive pharmacological property of amphetamines, which differ in this regard from other non-amphetamine substrates Hilber et al. The efflux is believed to be part of a more complex mechanism that includes a supplemental carrier trafficking induction associated with the alteration of presynaptic second messenger pathways. Therefore, critical interactions at SERT could be expected to be correlated with the differences among psychotropic amphetamines evidenced at the behavioral level. The results obtained in the present work agree with this assumption, as shown by the differences between MDMA and 2-Br-4,5-MDMA in key ecstasy-like behavioral paradigms. Interestingly, in the present study bromine substitution abolished the ability of acutely administered MDMA to increase locomotion already described by McCreary et al. The latter might be supported indirectly, at least in part, by the pharmacological effects reported for synthetic cathinones e. In particular, it has already been proposed that the unique locomotion activity pattern induced by MDMA in rodents seems to be strongly dependent on the differential activation of central D 1 , D 2 , and D 3 receptors Risbrough et al. The latter might be expressed as different availability ratios for dopamine and serotonin, as already reported for MDMA Baumann et al. As bromine substitution can be expected to modulate ligand affinity Hardegger et al. The latter may arise as a result of functional selectivity favoring alternative transduction pathways Moya et al. Active avoidance conditioning responses represent another key model for the evaluation of MDMA-like molecules, because the behavioral profile of MDMA in this protocol may be differentiated from those of structurally related stimulants and psychedelics. The binding and functional data reported in the present work support this notion. MDMA doses ranging from 2. Pro-social behavior is mediated by the activation of serotonergic 5-HT 1A receptors elicited indirectly by acute doses of MDMA after massive 5-HT release in the hypothalamus Morley et al. In this regard, one may speculate about a possible link between the amount of 5-HT released and the occurrence of specific pro-social behaviors. It should be noted that the entactogenic effects of MDMA in humans comprise a behavioral syndrome that may not be completely emulated in animal models. Nevertheless, social behavior has been used as a valuable tool in the preclinical testing of new drugs in laboratory animals. Indeed, an increase in social interaction has been shown to provide an index of potential anxiolytic activity Cutier, Consequently, any disruption of basal anxiety may be expected to affect social behavior. Two possible explanations may account for this apparent discrepancy: i firstly, bromination may have affected the ability of MDMA to cross the blood-brain barrier, thereby preventing 2-Br-4,5-MDMA from entering the brain, and ii secondly, bromination preserves the interaction of MDMA at SERT but may have altered the ability of MDMA to act as a substrate of the transporter i. Instead, the second alternative is more plausible. The behavioral effects of a SERT substrate may be produced by a non-exocytotic 5-HT release that could induce the activation of serotonergic receptors in the brain. Further experiments to fully characterize this qualitative change in the mode of binding at SERT are needed to confirm this possibility. Finally, and most interestingly, the results obtained in the present work indicate that the similarities between 2-Br-4,5-MDMA and citalopram offer some hints about the therapeutic potential of this new MDMA analog: on the one hand, its ability to act as a citalopram-like blocker of SERT suggests that it may act as an antidepressant; on the other hand, its strong inhibition of platelet aggregation might be consistent with an anticoagulant drug profile. These open possibilities deserve to be addressed further. In conclusion, and in contrast to our original hypothesis regarding the preservation or reinforcement of entactogenic qualities of MDMA, the results obtained in the present work are consistent with the notion that aromatic bromination of MDMA to give 2-Br-4,5-MDMA modulates its pharmacological features in a manner that resembles the effects of the SERT blocker citalopram, highlighting the relevance of this position on the aromatic ring as a key site to determine the mode of binding at SERT. The datasets generated for this study are available on request to the corresponding author. PS-B provided ideas or concepts for definition of intellectual context, particularly designed, and supervised the experiments. VC-C and BC performed the organic synthesis of compounds. RB and AH analyzed the data. PS-B wrote the manuscript. All authors read and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Alizadeh, A. Ando, R. Partial lesion of the serotonergic system by a single dose of MDMA results in behavioural desinhibition and enhances acute MDMA-induced social behavior on the social interaction test. Neuropharmacology 50, — Bankson, M. PubMed Abstract Google Scholar. Barfknecht, C. Potential psychotomimetics. Baumann, M. Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine MDMA is correlated with dialysate levels of serotonin and dopamine in rat brain. Baylen, C. Addiction , — Bicak, N. A new ionic liquid: 2-hydroxyethylammonium. Liquids , 15— Bouso, J. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Psychoactive Drugs 40, — Cheng, Y. Relationship between the inhibition constant K1 and the concentration of inhibitor which causes 50 per cent inhibition I50 of an enzymatic reaction. Coleman, J. X-ray structures and mechanism of the human serotonin transporter. Nature , — Crespi, D. Cutier, M. Measure of social interactions. Methods Neurosci. Danforth, A. MDMA-assisted therapy: a new treatment model for social anxiety in autistic adults. Psychiatry 64, — Doblin, R. Psychoactive Drugs 34, — Doly, S. Serotonin 5-HT2B receptors are required for 3,4methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. Dunlap, L. Dark classics in chemical neuroscience: 3,4-methylenedioxymetamphetamine. ACS Chem. Feduccia, A. Psychiatry 84, — Field, J. Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylenedioxymethamphetamine. File, S. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. Methods 2, — Gabrielsen, M. Substrate binding and translocation of the serotonin transporter studies by docking and molecular dynamics simulations. Galizio, M. Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats. Acute effects of the novel psychoactive drug 2C-B on emotions. Gouzoulis-Mayfrank, E. The contribution of human experimental studies to the classification of MDMA and other chemically related methylenedioxyamphetamine derivatives. Heffter Rev. Psychedelic Res. Google Scholar. Green, R. Hardegger, L. Systematic investigation of halogen bonding in protein—ligand interactions. Hilber, B. Serotonin-transporter mediated efflux: a pharmacological analysis of amphetamines and non-amphetamines. Neuropharmacology 49, — Kim, K. Inhibitory effects of black soybean on platelet activation mediated through its active component of adenosine. Liechti, M. Swiss Med. Lin, H. The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine. Marusich, J. Neuropharmacology 87, — Maurer-Spurej, E. Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection. Life Sci. McCreary, A. Mercado, C. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mithoefer, M. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Montgomery, T. Comparative potencies of 3,4-methylenedioxymethamphetamine MDMA analogues as inhibitors of \\\\\\\\\[3H\\\\\\\\\]noradrenaline and \\\\\\\\\[3H\\\\\\\\\]5-HT transport in mammalian cell lines. Mora, S. Effects of the estrous cycle and ovarian hormones on behavioral indices of anxiety in female rats. Psychoneuroendocrinology 21, — Morley, K. Serotonin 1A receptor involvement in acute 3,4-methylenedioxoymethamphetamine MDMA facilitation of the social interaction in the rat. Psychiatry 29, — Morris, K. UK places generic ban on mephedrone drug family. Lancet , — Moya, P. Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine 5-HT 2A and 5-HT2C receptors. Navarro, J. Psychiatry 26, — Nelson, D. Naunyn Schmiedebergs Arch. Nichols, D. Chemistry and structure-activity relationships of psychedelics. III, and Shulgin, A. Derivatives of 1- 1,3-benzodioxolyl butanamine: representative of a novel therapeutic class. Comparative study of the interactions of amphetamine derivatives with rat and human serotonin transporters through molecular modeling. Chile Parker, M. Synthesis and pharmacological evaluation of ring-methylated derivatives of 3,4- methylenedioxy -amphetamine MDA. Parrott, A. The psychotherapeutic potential of MDMA 3,4-methylenedioxy-methamphetamine : an evidence-based review. Psychopharmacology , — Pellow, S. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Methods 14, — Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Plenge, P. Riedlinger, T. Psychedelic and entactogenic drugs in the treatment of depression. Psychoactive Drugs 26, 41— Risbrough, V. Neuropsychopharmacology 3, — Rothman, R. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39, 32— Rudnick, G. Social interaction in rats as behavioral model for studying entactogenicity. Chile 5, 33— MDMA 3,4-methylenedioxymethamphetamine analogues as tools to characterize MDMA-like effects: an approach to understand entactogen pharmacology. New bromoalkoxyamphetamines. Sessa, B. Why MDMA therapy for alcohol use disorder? And why now? Neuropharmacology , 83— Shulgin, A. Berkeley, CA: Transform Press. Sitte, H. Amphetamine, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol. Thompson, M. Neuroscience , — Topiol, S. X-ray structure based evaluation of analogs of citalopram: compounds with increased affinity and selectivity compared with R-citalopram for the allosteric site S2 on SERT. Tseng, Y. A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation. Zhou, Z. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science , — 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. Cassels 6.
The Role of MDMA (Ecstasy) in Coping with Negative Life Situations Among Urban Young Adults
Купить шишки, бошки, гашиш Санта Лусия
The Role of MDMA (Ecstasy) in Coping with Negative Life Situations Among Urban Young Adults
Кокаин (VHQ, HQ, MQ, первый, орех) Тринкомали