Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by(+)-amphetamine, 3,4,-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine

Daniela Crespi, Tiziana Mennini, Marco Gobbi

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA ≤ MDMA ≤ (+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph > > pCA = MDMA > > (+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine).[3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31-80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]- dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ω-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. Methiothepin inhibited the Ca2+-dependent component of(S)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT(1/2), dopamine or any other extracellular receptor. These results indicate that the release induced by these compounds is both 'carrier-mediated' and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes.

Original languageEnglish
Pages (from-to)1735-1743
Number of pages9
JournalBritish Journal of Pharmacology
Volume121
Issue number8
DOIs
Publication statusPublished - 1997

Keywords

  • (+)-amphetamine
  • (+)-fenfluramine
  • 3,4-methylendioxymethamphetamine
  • 5-hydroxytryptamine release
  • 5-hydroxytryptamine transporters
  • Carrier-mediated release
  • Dopamine release
  • Dopamine transporters
  • Exocytotic release
  • P-chloroamphetamine

ASJC Scopus subject areas

  • Pharmacology

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