Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters

Hagino, Yoko; Takamatsu, Yukio; Yamamoto, Hiroyuki; Iwamura, Tatsunori; Murphy, Dennis L.; Uhl, George R.; Sora, Ichiro; Ikeda, Kazutaka

doi:10.2174/157015911795017254

Cited by 59 publications

(44 citation statements)

References 31 publications

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“…Microdialysis studies have shown an increase in synaptic DA and serotonin in the nucleus accumbens following exposure to MDMA, similarly to that seen with other addictive drugs (Cadoni et al, 2005;Colussi-Mas et al, 2010;Gudelsky and Yamamoto, 2008). A recent study has demonstrated the involvement of serotonin and DA transporters (SERT and DAT, respectively) in MDMA-induced DA release in the striatum, finding it to be blocked only in mice lacking both transporters, but not in those lacking either DAT or SERT (Hagino et al, 2011). In this way, disruption of DA and/or 5-HT neurotransmission impedes animals from experiencing the reinforcing effect of MDMA.…”

Section: Discussionmentioning

confidence: 84%

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Roger-Sánchez

Rodrı́guez-Arias

Miñarro

et al. 2013

Brain Research Bulletin

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Section: Discussionmentioning

confidence: 84%

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Roger-Sánchez

Rodrı́guez-Arias

Miñarro

et al. 2013

Brain Research Bulletin

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“…An established mechanism of MDMA- induced toxicity in the brain is an increase of extracellular 5-HT and DA levels via action on SERT and DAT both in vitro [57–60] and in vivo [61] with higher affinity binding to SERT [27]. MDMA also inhibits the enzyme monoamine oxidase [15] responsible for inactivation of serotonin and dopamine [62] that contributes to their elevated levels.…”

Section: Discussionmentioning

confidence: 99%

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells

et al. 2016

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3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

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“…The locomotor stimulant effects of MDMA are abolished in SERT KO mice (Bengel, et al, 1998), as is MDMA-induced serotonin release and MDMA self-administration (Trigo, et al, 2007). Surprisingly, and perhaps indicating non-SERT mediated mechanisms in some of the effects of MDMA, increases in extracellular dopamine levels in the nucleus accumbens in SERT KO mice after administration of MDMA are unchanged (Trigo, et al, 2007) or reduced (Hagino, et al, 2011). In the latter study, the effects of MDMA on dopamine release were only eliminated in combined DAT/SERT KO mice.…”

Section: Modeling Candidate Genes With Knockout (Ko) Micementioning

confidence: 98%

Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?

Hall

Drgonová

Jain

et al. 2013

Pharmacology & Therapeutics

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Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS.

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Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters

Cited by 59 publications

References 31 publications

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells

Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?

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