Invited Symposium: Molecular and Cellular Analysis of Dopamine and Serotonin Transporters
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:
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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|Gobbi, M; Dalla Valle, F; Ciapparelli, C; Mennini, T; (1998). Role of the 5-HT Transporter in the Drug-Induced 'Carrier-Dependent' Release. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/simantov/gobbi0727/index.html|
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