Thioether Metabolites of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine Inhibit Human Serotonin Transporter (hSERT) Function and Simultaneously Stimulate Dopamine Uptake into hSERT-Expressing SK-N-MC Cells

Jones, Douglas C.; Lau, Serrine S.; Monks, Terrence J.

doi:10.1124/jpet.104.069260

Cited by 45 publications

(26 citation statements)

References 39 publications

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“…It has been postulated that a neurotoxic metabolite of MDMA, formed peripherally, mediates the toxicity of this amphetamine analog (Jones et al, 2004). In view of the present finding that coperfusion of malonate and MDMA does deplete brain 5-HT, in accordance with Nixdorf et al (2001), it can be speculated that such a neurotoxic metabolite of MDMA may have detrimental effects on mitochondrial function that promote neurotoxicity.…”

Section: Discussionmentioning

confidence: 48%

Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

Darvesh

Yamamoto

Gudelsky

2004

J Pharmacol Exp Ther

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Production of reactive oxygen and/or nitrogen species has been thought to contribute to the long-term depletion of brain dopamine and serotonin (5-HT) produced by amphetamine derivatives, i.e., methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). In the present study, the effects of nitric-oxide synthase (NOS) inhibitors were examined on the long-term depletion of striatal dopamine and/or 5-HT produced by the local perfusion of malonate and MDMA or the systemic administration of MDMA. The effect of MDMA on nitric oxide formation and nitrotyrosine concentration also was determined. Perfusion with MDMA and malonate resulted in a 34% reduction of 5-HT and 49% reduction of dopamine concentrations in the striatum. The systemic administration of NOS inhibitors, N-nitro-L-arginine methyl ester hydrochloride and S-methyl-Lthiocitrulline (S-MTC), and the peroxynitrite decomposition catalyst Fe(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride attenuated the MDMA-and malonate-induced depletion of striatal dopamine and 5-HT. S-MTC also attenuated the depletion of 5-HT in the striatum produced by the systemic administration of MDMA without attenuating MDMA-induced hyperthermia. Additionally, the systemic administration of MDMA significantly increased the formation of nitric oxide and the nitrotyrosine concentration in the striatum. These results support the conclusion that MDMA produces reactive nitrogen species in the rat that contribute to the neurotoxicity of this amphetamine analog.

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Section: Discussionmentioning

confidence: 48%

Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

Darvesh

Yamamoto

Gudelsky

2004

J Pharmacol Exp Ther

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“…More recently, it was demonstrated that MDMA-induced 5-HT depletion observed in wild-type mice did not occur in MAO-Bdeficient mice (Fornai et al, 2001) and that an antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA (Falk et al, 2002). Moreover, it was also shown that dopamine uptake into serotonergic nerve endings, followed by MAO-B metabolism and subsequent oxidative stress also contributes to the neurotoxic effects of MDMA (Hrometz et al, 2004;Jones et al, 2004). Thus, it may be assumed that MAO-B-mediated metabolism of monoamine neurotransmitters following their vesicular release by MDMA is an important driving factor for MDMA-induced neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria

Alves¹,

Summavielle²,

Alves³

et al. 2007

J. Neurosci.

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“…2,19) In contrast, SERT, NET, and DAT have much higher affinity for the corresponding monoamines, and the K m values are several hundred or thousand nanomoles. [20][21][22] Therefore, monoamine neurotransmitters could be mainly eliminated from the synaptic cleft by SERT, NET, and DAT, but not by OCT2 and -3, under normal conditions. The low-affinity transporters would not contribute to the uptake of monoamines in the synaptic cleft owing to the existence of the high-affinity transporters.…”

Section: Physiological Roles Of Organic Cation Transporters In Neuronsmentioning

confidence: 99%

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Nakamichi

Kato

2017

Biological & Pharmaceutical Bulletin

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Dysfunction in neurotransmission mediated by neurotransmitters causes various neurological disorders.Therefore, receptors and reuptake transporters of neurotransmitters have been focused on as a therapeutic target in neurological disorders. These membrane proteins have high affinity for a specific neurotransmitter and are highly expressed on synaptic membranes. In contrast, xenobiotic transporters have relatively lower affinity for neurotransmitters but widely recognize various organic cations and/or anions and are also expressed in brain neurons. However, it has been largely unknown why such xenobiotic transporters are expressed in neurons that play a key role in signal transduction. We have therefore attempted to clarify the physiological roles of one such xenobiotic organic cation transporter (OCT) in neural cells with the aim of obtaining new insight into the treatment of neurological disorders. Carnitine/organic cation transporter OCTN1/SLC22A4 is functionally expressed in neurons and neural stem cells. In particular, OCTN1 is expressed at much higher levels compared with other OCTs in neural stem cells and positively regulates their differentiation into neurons. OCTN1 accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a good in vivo substrate. Because ERGO is highly distributed into the brain after oral ingestion, OCTN1 may contribute to the alleviation of oxidative stress and promotion of neuronal differentiation via the uptake of ERGO in the brain, perhaps abating symptoms of neurological disorders. In this review, we introduce current topics on the physiological roles of OCTs with a focus on OCTN1 in neural cells and discuss its possible application to the treatment of neurological disorders.

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Thioether Metabolites of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine Inhibit Human Serotonin Transporter (hSERT) Function and Simultaneously Stimulate Dopamine Uptake into hSERT-Expressing SK-N-MC Cells

Cited by 45 publications

References 39 publications

Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

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