Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
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The concept that the neurotransmitter reuptake carriers can, in certain conditions, transport the neurotransmitter outside the nerve endings are well estabilished: this may happen when the Na+ gradient decreases, when the cytoplasmic concentrations of free neurotransmitter increase or in the presence of substrates of the carrier (for a review: Levi and Raiteri, 1993).

Amphetamine and its analogue d-fenfluramine (dF) are substrates of dopamine (DA) and serotonin (5-HT) transporters, respectively, and induce a carrier-mediated monoamine release whose mechanism is though to involve the following steps:

1. Entry of these drugs into the nerve ending as substrates of the specific carrier or by diffusion
2. Drug-induced monoamine release from intracellular storage vesicles, resulting in the increase of cytoplasmic monoamine concentration;
3. Carrier-mediated outward transport of the monoamine.

These steps have been clearly demonstrated using "artificial" experimental models (i.e. vesicles and transfected cells). However, it is necessary to verify them in more intact systems. Synaptosomes may be considered the simplest of these intact systems: they have the native transporters with a physiological density, they store the neurotransmitter in the synaptic vesicles and they possess the enzymes metabolizing the cytoplasmic monoamine.

Therefore, in the present work we re-evaluated the requirements for having a "carrier-mediated" monoamine release using superfused synaptosomes preloaded with [³H]5-HT. We considered the relative role of the increased cytoplasmic 5-HT concentration and/or of the presence of a carrier substrate, by comparing the releasing effect of dF (substrate of the carrier with vesicle-depleting action) with that of RO4-1284, a vesicular monoamine transporter type-II inhibitor, (only vesicle-depleting action). These experiments were carried out in the absence or presence of pargyline (a MAO inhibitor) which also allowed us to analyze the relative effectiveness of the 5-HT metabolism as compared with the carrier-mediated outward transport of 5-HT.

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