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

Abstract

1 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. 2 Their rank order of potency for [³H]‐5‐HT‐releasing activity was the same as for inhibition of 5‐HT uptake (pCAMDMA(+)‐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). 3 [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. 4 Methiothepin inhibited the Ca²⁺‐dependent component of (+)‐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. 5 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. British Journal of Pharmacology (1997) 121, 1735–1743; doi:10.1038/sj.bjp.0701325