Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
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Both dF and Ro4-1284 induce a rapid (within few min in our conditions) release of 5-HT from storage vesicles to the cytoplasm.

In the absence of pargyline, such an increase of cytoplasmic 5-HT is followed by:

• a rapid carrier-mediated 5-HT release in the presence of a substrate of the carrier (i.e. dF)

• a rapid MAO-metabolism followed by a rapid 5-HIAA diffusion outside the nerve ending in the absence of a substrate of the carrier (i.e. with RO4-1284)

Thus, the increased cytoplasmic 5-HT concentration is per se not sufficient to activate a carrier-mediated transport of 5-HT; but in the presence of a substrate, the carrier-mediated 5-HT release is more rapid than 5-HT metabolism.

In the presence of pargyline, RO4-1284 induced a carrier-independent [³H]5-HT release, suggesting that cytoplasmic 5-HT may cross the plasma membrane by a carrier-independent route, which is delayed as compared to the carrier-dependent way active in the presence of a carrier substrate. Such a finding had been previously described in cells (Cinquanta et al., 1996) and in slices (Reimann and Schneider, 1998). However, when allowed (in the absence of pargyline) the 5-HT metabolism appeared to be more rapid than the carrier-independent 5-HT efflux.

Some of these conclusions are at variance with those suggested by Jones et al. (1998), by studying the endogenous DA-induced release from slices. In particular they found:

• a lack of the DA-releasing effect of Ro4-1284 either in the presence or in the absence of pargyline (in preliminar experiments we found a marked and rapid tritium release also from [3H]DA preloaded striatal synaptosomes). Moreover, in the absence of pargyline, the cytoplasmic DA (increased by Ro4-1284) could persist for a long period (> 10 min) without being metabolized.
• a delayed (>10 min) amphetamine-induced release, which was interpreted suggesting that the amphetamine vesicle-depleting action is the rate-limiting step of the whole release effect.

It would be important to understand the reason for these discrepancies, which might be accounted for by:

• differences between the experimental models (i.e. the possibility of a reuptake of the released neurotrasmitter is likely using slices but not using superfused synaptosomes; or the labeled neurotransmitter might be stored in a subpopulation of vesicles more accessible to amphetamines (Anderson et al., 1998) than the endogenous neurotransmitter).
• differences between dF and amphetamine;
• differences between DAergic and 5-HTergic nerve endings.

Acknowledgements:

We thank Dr. Alessandro Barazzetti and Dr. Stefano Ambrosio for the assistance in the preparation of the HTML document

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