Separating the agony from ecstasy: R(–)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

Curry, Daniel W.; Young, Matthew B.; Tran, Andrew; Daoud, Georges; Howell, Leonard L.

doi:10.1016/j.neuropharm.2017.10.003

Cited by 36 publications

(30 citation statements)

References 58 publications

(79 reference statements)

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“…Although we did not observe a significant increase in locomotor activity following MDMA, this finding is consistent with the complex locomotor profile of MDMA reported in rodents (17,27).…”

supporting

confidence: 92%

“…Because octopuses are thought to be the most behaviorally advanced invertebrates, this resource enables testing of molecular homology for complex behaviors, despite anatomical differences in brain organization across evolutionarily distant lineages (14). In this context, it is interesting to note that in vertebrates (humans and rodents), the atypical amphetamine derivative (+/-)-3,4methylendioxymethamphetamine (MDMA) is known for its powerful prosocial properties (15)(16)(17). Furthermore, the sixth trans-membrane domain (TM6) of the serotonin transporter (SERT), encoded by the SLC6A4 gene (18), has been identified as the principle binding site of MDMA (19)(20)(21).…”

mentioning

confidence: 99%

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SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides

Edsinger¹,

Dölen

2018

Preprint

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ABSTRACT:Human and octopus lineages are separated by over 500 million years of evolution, and show divergent anatomical patterns of brain organization. Moreover, while humans exhibit highly complex social behaviors, octopuses are thought to be largely asocial and solitary. Despite these differences, growing evidence suggests that ancient neurotransmitter systems are shared across vertebrate and invertebrate species, and in many cases enable overlapping functions. Here we provide evidence that, as in humans, the atypical amphetamine derivative (+/-)-3,4-methylendioxymethamphetamine (MDMA) enhances acute prosocial behaviors in Octopus bimaculoides. This finding is paralleled by the evolutionary conservation of the serotonin transporter (SERT, encoded by the Slc6A4 gene) binding site of MDMA in the O. bimaculoides genome. Taken together, these data provide evidence that the neural mechanisms subserving social behaviors exist in O. bimaculoides, and indicate that the role of serotonergic neurotransmission in regulating social behaviors is evolutionarily conserved.ONE SENTENCE SUMMARY:Here we provide evidence that the atypical amphetamine derivative (+/-)-3,4-methylendioxymethamphetamine (MDMA) increases acute social approach behaviors in Octopus bimaculoides, a finding that is paralleled by the evolutionary conservation of the SLC6A4 binding site of MDMA.

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“…Although we did not observe a significant increase in locomotor activity following MDMA, this finding is consistent with the complex locomotor profile of MDMA reported in rodents (17,27).…”

supporting

confidence: 92%

mentioning

confidence: 99%

SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides

Edsinger¹,

Dölen

2018

Preprint

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“…254 Furthermore, the R -enantiomer did not increase locomotor activity, a behavioral effect commonly produced by psychostimulants. 254 …”

Section: S-(+)-mdma Vs R-(−)-mdmamentioning

confidence: 95%

“…To more definitely establish a lack of neurotoxicity following R -(−)-MDMA administration, Howell and co-workers administered high doses of R -(−)-MDMA (four injections of 50 mg/kg given over two days) to mice and compared effects to those produced by the racemic mixture (four injections of 20 mg/kg given over two days). 254 These authors assessed body temperature, mortality, and markers of neurotoxicity. Unlike the racemate, high dose R -(−)-MDMA did not influence body temperature or survival.…”

Section: S-(+)-mdma Vs R-(−)-mdmamentioning

confidence: 99%

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

Dunlap

Andrews

Olson

2018

ACS Chem. Neurosci.

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Better known as “ecstasy,” 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today’s teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science—having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.

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“…The mice were then placed in the testing box, allowed to acclimatize in the box for 5 min and video recorded for 10 min. Behavior was rated on a 6-point scale, composed of: adjacent lying, anogenital sniffing, general investigation, body crossing, aggression, and no social interaction, as has been done previously (Curry et al, 2018). The 50 μg dose of OT was based on preliminary social-behavior experiments.…”

Section: Social Behaviormentioning

confidence: 99%

Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin

Oppong‐Damoah

Zaman

D’Souza

et al. 2019

Hormones and Behavior

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The blood-brain barrier (BBB) limits the therapeutic use of large molecules as it prevents them from passively entering the brain following administration by conventional routes. It also limits the capacity of researchers to study the role of large molecules in behavior, as it often necessitates intracerebroventricular administration. Oxytocin is a large-molecule neuropeptide with pro-social behavioral effects and therapeutic promise for social-deficit disorders. Although preclinical and clinical studies are using intranasal delivery of oxytocin to improve brain bioavailability, it remains of interest to further improve the brain penetrance and duration of action of oxytocin, even with intranasal administration. In this study, we evaluated a nanoparticle drug-delivery system for oxytocin, designed to increase its brain bioavailability through active transport and increase its duration of action through encapsulation and sustained release. We first evaluated transport of oxytocin-like large molecules in a cell-culture model of the BBB. We then determined in vivo brain transport using bioimaging and cerebrospinal fluid analysis in mice. Finally, we determined the pro-social effects of oxytocin (50 μg, intranasal) in two different brain targeting and sustainedrelease formulations. We found that nanoparticle formulation increased BBB transport both in vitro and in vivo. Moreover, nanoparticle-encapsulated oxytocin administered intranasally exhibited greater pro-social effects both acutely and 3 days after administration, in comparison to oxytocin alone, in mouse social-interaction experiments. These multimodal data validate this brain targeting and sustained-release formulation of oxytocin, which can now be used in animal models of social-deficit disorders as well as to enhance the brain delivery of other neuropeptides.

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Separating the agony from ecstasy: R(–)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

Cited by 36 publications

References 58 publications

SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides

SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin

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