Carrier‐dependent and Ca 2+ ‐dependent 5‐HT and dopamine release induced by (+)‐amphetamine, 3,4‐methylendioxy‐methamphetamine, p ‐chloroamphetamine and (+)‐fenfluramine

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 3 H neurotransmitters. 2 Their rank order of potency for [ 3 H]‐5‐HT‐releasing activity was the same as for inhibition of 5‐HT uptake (pCAMDMA(+)‐Fen>>(+)‐Amph). Similarly, their rank order as [ 3 H]‐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 [ 3 H]‐5‐HT and/or [ 3 H]‐dopamine release induced by all these compounds was partially (31–80%), but significantly Ca 2+ ‐dependent. Lack of extracellular Ca 2+ did not alter uptake mechanisms nor did it modify the carrier‐dependent dopamine‐induced [ 3 H]‐dopamine release. (+)‐Amph‐induced [ 3 H]‐dopamine release and pCA‐ and MDMA‐induced [ 3 H]‐5‐HT release were significantly inhibited by ω‐agatoxin‐IVA, a specific blocker of P‐type voltage‐operated Ca 2+ ‐channels, similar to the previous results on (+)‐Fen‐induced [ 3 H]‐5‐HT release. 4 Methiothepin inhibited the Ca 2+ ‐dependent component of (+)‐Amph‐induced [ 3 H]‐dopamine release with high potency (70 n M ), as previously found with (+)‐Fen‐induced [ 3 H]‐5‐HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca 2+ ‐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 Ca 2+ ‐dependent (possibly exocytotic‐like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca 2+ ‐dependent release is mediated by Ca 2+ ‐influx (mainly through P‐type Ca 2+ ‐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