Inhibition of vesicular storage

Inhibition of vesicular storage

Vesicular accumulation of catecholamines and of serotonin is inhibited by reserpine (Figure 10.14a). While reserpine initially was believed to inhibit the H⁺-ATP'ase that gener-ates and maintains a high proton concentration inside the vesicles⁶, it is now clear that reserpine instead binds to the vesicular transmitter transporter that makes use of this pro-ton gradient to move the transmitter uphill its own gradi-ent into the vesicle (Figure 10.14b). The number of protons released for the import of each transmitter molecule is not known with certainty but is likely greater than 1.

Reserpine affects both the central nervous system⁷ and the peripheral autonomic system. The immediate effect will be the accumulation of transmitter in the cytosol. From there, it may `spill over', possibly by retrograde operation of the specific reuptake transporters, into the synaptic cleft. Accordingly, a transient `sympathomimetic' effect may be seen after application of a high dosage of reserpine. How-ever, the cytosolic transmitter excess will soon be scav-enged by increased breakdown and inhibition of synthesis, and the main effect of inhibited synaptic transmission will become manifest (Figure 10.14c). The action of reserpine was initially observed in an extract of the Indian plant Rau-wolfia serpentina, which was noticed to have antipsychotic effects⁸. After it was purified, the drug was used initially in the same application but later on was mainly used for anti-hypertensive treatment. It now has largely been abandoned in favour of more selective agents.