title: 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.
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 [(3)H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA >> MTA > or = 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 V(max) 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.
authors.affiliation: Istituto di Ricerche Farmacologiche "Mario Negri", Italy. Gobbi@marionegri.it
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Marcella
authors.initials: M
authors.lastname: Funicello
authors.forename: Klaus
authors.initials: K
authors.lastname: Gerstbrein
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.forename: Pablo R
authors.initials: PR
authors.lastname: Moya
authors.forename: Ramón
authors.initials: R
authors.lastname: Sotomayor
authors.forename: María Inés
authors.initials: MI
authors.lastname: Forray
authors.forename: Katia
authors.initials: K
authors.lastname: Gysling
authors.forename: Silvio
authors.initials: S
authors.lastname: Paluzzi
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Parada
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
mesh_terms: D000661:Amphetamine / Q000737:chemistry / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism* / Q000502:physiology; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D000662:Amphetamines; C000593771:N,N-dimethylthioamphetamine; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; C078956:4-methylthioamphetamine; D000661:Amphetamine