Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

Dunlap, Lee E.; Andrews, Anne M.; Olson, David E.

doi:10.1021/acschemneuro.8b00155

Cited by 69 publications

(88 citation statements)

References 248 publications

(563 reference statements)

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“…Moreover, because these effects were reported to be different compared to those expected for structurally related psychedelics (Nichols and Glennon, 1984), it was proposed that the unique behavioral effects of MDMA might be mediated through its actions at SERT (Rudnick and Wall, 1992). 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, 2010; Dunlap et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…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. Regarding the latter, it should be noted that the behavioral characterization of ecstasy has been attempted in different animal models, producing heterogeneous results that depend on several factors, such as dosage regimen, animal species or administration routes (Sáez-Briones and Hernández, 2013; Dunlap et al, 2018). Nevertheless, and for the purpose of the present work, a behavioral profile of MDMA in rats after acute administration based on complete dose-effect curves under the same experimental conditions has been used to evaluate the influence of aromatic bromination (Quinteros-Muñoz et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

et al. 2019

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The entactogen MDMA (3,4-methylenedioxy-methamphetamine, “Ecstasy”) exerts its psychotropic effects acting primarily as a substrate of the serotonin transporter (SERT) to induce a non-exocytotic release of serotonin. 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. In the present work, a new MDMA analog brominated at C(2) of the aromatic ring (2-Br-4,5-MDMA) has been synthesized and pharmacologically characterized in vitro and in vivo . First, binding competition experiments against the SERT-blocker citalopram were carried out in human platelets and compared with MDMA. 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. The results obtained showed that 2-Br-4,5-MDMA exhibits higher affinity for SERT than MDMA and fully abolishes both platelet aggregation and ATP release, resembling the pharmacological profile of citalopram. 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. Taken together, the results obtained are consistent with the notion that 2-Br-4,5-MDMA should not be expected to be an MDMA-like substrate of SERT, indicating that aromatic bromination at C(2) modulates the pharmacodynamic properties of the substrate MDMA, yielding a citalopram-like compound.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

et al. 2019

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“…Furthermore, MDMA has demonstrated great promise in the clinic for treating PTSD via a treatment paradigm that can best be described as pharmaceutical-enhanced psychotherapy. 9 The use of psychoplastogens to enhance fear extinction is gaining traction and in principle, the same strategy could be used to extinguish drug-cue memories. Perhaps, this is why psychedelic compounds such as DMT, ibogaine, and LSD have shown promise for treating substance use disorders.…”

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confidence: 99%

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

2018

Self Cite

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Neural plasticity—the ability to change and adapt in response to stimuli—is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens—a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.

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“…Il semblerait que l'aptitude de la MDMA à favoriser l'extinction soit médiée par la sérotonine et les récepteurs 5-HT 2A , car leur inhibition limite son efficacité (Young et al, 2017). Les effets de cette drogue sur les neurotrophines ne sont pas clairement établis du fait de la variabilité des protocoles et des doses, d'autant plus que les fortes doses et/ou l'administration répétée sont neurotoxiques (Dunlap et al, 2018).…”

Section: 4-méthylènedioxyméthamphétamine Et Neurotrophinesunclassified

Utilisation des psychédéliques en psychiatrie : lien avec les neurotrophines

Corne

Mongeau

2019

Biologie Aujourd’hui

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Reçu le 29 avril 2019Résumé --Les psychédéliques, souvent appelés hallucinogènes, sont une classe de psychotropes très singulière. Les effets subjectifs et comportementaux qu'ils induisent sont très impressionnants, et malgré leur toxicité potentielle, le risque d'addiction est relativement faible par rapport à la nicotine, l'alcool ou les opiacés. Depuis la découverte des effets antidépresseurs de la kétamine, il existe un regain d'intérêt pour cette classe de molécules. En effet, la psilocybine et l'acide lysergique diéthylamide (LSD) gagnent de la popularité en tant que traitement pour la dépression et l'addiction, la 3,4-méthylènedioxyméthamphétamine (MDMA) pour l'état de stress post-traumatique, et l'ibogaïne pour l'addiction. Malgré des profils pharmacologiques distincts, ces différentes drogues partagent une cinétique d'action similaire : leurs effets thérapeutiques se font ressentir dans les heures suivant l'administration et perdurent au-delà de leur élimination par l'organisme. Ceci suggère des mécanismes plastiques et neurogéniques impliquant entre autres des facteurs trophiques. Cette revue explorera la littérature concernant les effets de ces différents composés sur les neurotrophines, ainsi que les adaptations plastiques qui sont mises en place dans les heures et jours suivant l'administration, afin de comprendre leur potentiel thérapeutique étonnant. Abstract --Neurotrophic mechanisms of psychedelic therapy. Psychedelic drugs, often referred to as hallucinogens, are quite distinct from other classes of psychotropic drugs. Although the subjective and behavioral effects they induce are quite dramatic, they possess little addictive potential when compared to nicotine, alcohol or opiates. Since the discovery of ketamine antidepressant effects, there has been growing interest for these molecules. Serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are gaining attention as potential treatments for depression and addiction, similarly to 3,4-methylenedioxymethamphetamine (MDMA) for post-traumatic stress disorder (PTSD), and ibogaine for addiction. Although they possess distinct pharmacological profiles, their kinetics of action are quite similar: the therapeutic effects are felt within the hours following administration, and last well beyond drug elimination by the organism. This strongly suggests the induction of neurogenic and plastic mechanisms, including the involvement of trophic factors. This review will explore the literature dealing with the effects of psychedelics on neurotrophins, as well as the plastic adaptations that they induce, in an attempt to understand their surprising therapeutic potential. We will show that although ketamine and serotonergic psychedelics have affinity for very different receptors (NMDA, 5-HT2A), they ultimately initiate similar plastic adaptations in the prefrontal cortex through the involvement of the brain-derived neurotrophic factor (BDNF). We will see that although MDMA uses the same receptors as serotonergic psychedelics to alleviate P...

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Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

Cited by 69 publications

References 248 publications

Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

Utilisation des psychédéliques en psychiatrie : lien avec les neurotrophines

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