N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents

Marco Gobbi, Marcella Funicello, Klaus Gerstbrein, Marion Holy, Pablo R. Moya, Ramón Sotomayor, María Inés Forray, Katia Gysling, Silvio Paluzzi, Giambattista Bonanno, Miguel Reyes-Parada, Harald H. Sitte, Tiziana Mennini

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

We studied two non-neurotoxic amphetamine derivatives (methyl- thioamphetamine, MTA and N,N-dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p-Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [3H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA » MTA ≥ DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose-response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a Vmax 40% lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as 'partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties.

Original languageEnglish
Pages (from-to)1770-1780
Number of pages11
JournalJournal of Neurochemistry
Volume105
Issue number5
DOIs
Publication statusPublished - Jun 2008

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Pemetrexed
Amphetamine
Serotonin
Substrates
HEK293 Cells
Derivatives
Synaptosomes
In Vitro Techniques
Oocytes
Rats
Brain

Keywords

  • Methyl-thioamphetamine
  • N,N-dimethyl-thioamphetamine
  • Neurotoxicity
  • p-Cl-amphetamine
  • Serotonin release
  • Serotonin transporters

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents. / Gobbi, Marco; Funicello, Marcella; Gerstbrein, Klaus; Holy, Marion; Moya, Pablo R.; Sotomayor, Ramón; Forray, María Inés; Gysling, Katia; Paluzzi, Silvio; Bonanno, Giambattista; Reyes-Parada, Miguel; Sitte, Harald H.; Mennini, Tiziana.

In: Journal of Neurochemistry, Vol. 105, No. 5, 06.2008, p. 1770-1780.

Research output: Contribution to journalArticle

Gobbi, M, Funicello, M, Gerstbrein, K, Holy, M, Moya, PR, Sotomayor, R, Forray, MI, Gysling, K, Paluzzi, S, Bonanno, G, Reyes-Parada, M, Sitte, HH & Mennini, T 2008, 'N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents', Journal of Neurochemistry, vol. 105, no. 5, pp. 1770-1780. https://doi.org/10.1111/j.1471-4159.2008.05272.x
Gobbi, Marco ; Funicello, Marcella ; Gerstbrein, Klaus ; Holy, Marion ; Moya, Pablo R. ; Sotomayor, Ramón ; Forray, María Inés ; Gysling, Katia ; Paluzzi, Silvio ; Bonanno, Giambattista ; Reyes-Parada, Miguel ; Sitte, Harald H. ; Mennini, Tiziana. / N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents. In: Journal of Neurochemistry. 2008 ; Vol. 105, No. 5. pp. 1770-1780.
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abstract = "We studied two non-neurotoxic amphetamine derivatives (methyl- thioamphetamine, MTA and N,N-dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p-Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [3H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA » MTA ≥ DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose-response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a Vmax 40{\%} lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as 'partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties.",
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T1 - N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents

AU - Gobbi, Marco

AU - Funicello, Marcella

AU - Gerstbrein, Klaus

AU - Holy, Marion

AU - Moya, Pablo R.

AU - Sotomayor, Ramón

AU - Forray, María Inés

AU - Gysling, Katia

AU - Paluzzi, Silvio

AU - Bonanno, Giambattista

AU - Reyes-Parada, Miguel

AU - Sitte, Harald H.

AU - Mennini, Tiziana

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N2 - We studied two non-neurotoxic amphetamine derivatives (methyl- thioamphetamine, MTA and N,N-dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p-Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [3H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA » MTA ≥ DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose-response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a Vmax 40% lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as 'partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties.

AB - We studied two non-neurotoxic amphetamine derivatives (methyl- thioamphetamine, MTA and N,N-dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p-Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [3H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA » MTA ≥ DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose-response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a Vmax 40% lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as 'partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties.

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