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 (+)-fen¯uramine ((+)-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 (pCA5MDMA5(+)-Fen44(+)-Amph). Similarly, their rank order as [ 3 H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph44pCA=MDMA44(+)-Fen). We also con®rmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). The inhibitory e ect of methiothepin was not due to its e ects 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 speci®c carrier allowing the amphetamines to enter the synaptosome. The Ca 2+ -dependent release is mediated by Ca 2+ -in¯ux (mainly through P-type Ca 2+ -channels), possibly triggered by the drug interacting with an unknown intracellular target, a ected by methiothepin, common to both 5-HT and dopamine synaptosomes.

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

“…In addition to the experiments with fenfluramine further evidence that [ 3 H]N-methylspiperone was insensitive to manipulation of 5-HT levels was provided by the experiments with p-choroamphetamine. Although this compound releases 5-HT with a potency which is about twice that of fenfluramine (Crespi et al 1997), in the present study it did not affect the in vivo [ 3 H]N-methylspiperone binding.…”

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

“…Under in vitro conditions, the release of 5-HT is increased from brain slices, synaptosomes and cultured neurons following exposure to MDMA (Nichols et al, 1982;Johnson et al, 1986;Berger et al, 1997;Crespi et al, 1997;Azmitia et al, 1990;Sprouse et al, 1989). The MDMA-induced release of 5-HT in vitro is suppressed in the presence of drugs that inhibit the activity of the 5-HT transporter indicating that the increase in release of 5-HT likely occurs through the 5-HT transporter (Hekmatpanah and Peroutka, 1990;Gu and Azmitia, 1993;Koch and Galloway, 1993).…”

“…Striatum-Under in vitro conditions MDMA has been shown to promote the release of DA from superfused brain slices, as well as prevent the reuptake of DA into brain synaptosomes (Johnson et al, 1986;Schmidt et al, 1987;Johnson et al, 1991;Steele et al, 1987). Moreover, Crespi et al (1997) demonstrated that the MDMA-induced release of DA from striatal synaptosomes is carrier-mediated and calcium dependent. Yamamoto and Spanos (1988) using in vivo voltammetry were among the first to demonstrate that MDMA at behaviorally relevant doses (i.e., 5-10 mg/kg) increases the release of striatal DA in vivo.…”

Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

“…Although PCA also causes an acute release of dopamine (DA) (Crespi et al 1997;Henderson et al 1993;Johnson et al 1990;Ögren 1985b;Sharp et al 1986) as well noradrenaline (NA) (Ögren 1982; Ögren 1985a) in the rat brain, its behavioral effects are mediated primarily via serotonergic mechanisms (Adell et al 1989;Geyer 1996;Hutson and Curzon 1989;Trulson and Jacobs 1976). In support of this, the one-way active avoidance deficit by PCA was completely blocked when the rats were pretreated with 5-HT reuptake inhibitors zimeldine and fluoxetine but not by the NA uptake inhibitor desipramine (Ögren 1982).…”