CARRIER-DEPENDENT AND CA2-DEPENDENT 5-HT AND DOPAMINE RELEASE INDUCEDBY (+)-AMPHETAMINE, 3,4-METHYLENDIOXYMETHAMPHETAMINE, P-CHLOROAMPHETAMINE AND(+)-FENFLURAMINE()

1 The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymetham phetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)- Fen) was investigated in rat brain superfused synaptosomes preloaded w ith the H-3 neurotransmitters. 2 Their rank order of potency for [H-3] -5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA greater than or equal to MDMA greater than or equal to(+)-Fen>>( +)-Amph). Similarly, their rank order as [H-3]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was pre vented by selective transporter inhibitors (indalpine or nomifensine). 3 [H-3]-5-HT and/or [H-3]-dopamine release induced by all these compo unds 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 [H-3]-dopamine release. (+)-Amp h-induced [H-3]dopamine release and pCA-and MDMA-induced [H-3]-5-HT re lease were significantly inhibited by omega-agatoxin-IVA, a specific b locker of P-type voltage-operated Ca2+-channels, similar to the previo us results on (+)-Fen-induced [H-3]-5-HT release. 4 Methiothepin inhib ited the Ca2+-dependent component of(+)-Amph-induced [H-3]-dopamine re lease with high potency (70 nM), as previously found with(+)-Fen-induc ed [H-3]-5-HT release. The inhibitory effect of methiothepin was not d ue to its effects as a transporter inhibitor or Ca2+-channel blocker a nd is unlikely to be due to its antagonist properties on 5-HT1/2, dopa mine or any other extracellular receptor. 5 These results indicate tha t the release induced by these compounds is both 'carrier-mediated' an d Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependen t release is mediated by Ca2+-influx (mainly through P-type Ca2+-chann els), possibly triggered by the drug interacting with an unknown intra cellular target, affected by methiothepin, common to both 5-HT and dop amine synaptosomes.