The role of the vesicular monoamine transporter 2 in the inhibitory effect of tetrabenazine and valbenazine compared to reserpine on the vesicular release of monoamine transmitters.

Background: Vesicular monoamine transporter 2 (VMAT-2) plays a vital role in packaging cytosolic monoamine transmitters into axon terminal vesicles, which can be released in response to action potentials. Reserpine (RSP), a classical irreversible inhibitor of the monoamine transporter, is an alkaloid used as an antihypertensive drug. However, its use in medicine was very short-lived because of side effects (depression, Parkinsonism). Tetrabenazine (TBZ) and valbenazine (VBZ), biochemically non-competitive and reversible VMAT-2 inhibitors, are both used in the treatment of Tardive Dyskinesia (TD). The aim of this study was to directly compare the effects of RSP, TBZ, and VBZ on vesicular storage and exocytotic release of monoamines in hippocampal slices, and to clarify whether their actions differ in terms of reversibility and persistence. Our work addresses the biological question of how these clinically relevant VMAT-2 inhibitors modulate monoaminergic neurotransmission at the synaptic level. Materials and methods: Vesicular storage capacity and release of [ Results: In this study, for the first time, direct neurochemical evidence was obtained that RSP reduces the vesicular storage capacity and the exocytotic release of [ Discussion: The difference observed between the two types of VMAT-2 inhibitors might give some explanation of why, in response to TBZ or VBZ treatment, the occurrence of depression or Parkinsonism as side effects is seen very rarely or not at all, and in the case of RSP, it is relatively frequent.