Study of the Vesicular Monoamine Transporter: Role and Function

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Synthesized in only a few restricted nuclei in the brain, the three monoamines (MA) neurotransmitters, dopamine, serotonin and noradrenalin, are altogether the major regulators of almost all superior brain functions. The importance of MA neurotransmission is highlighted by their direct implication in functions as diversed as sleep processes, executive functions, learning and memory, pain, anxiety, arousal, motivation, locomotor control, reward, etc etc.... At the present time, more than 80% of psychotropic or recreative drugs that are used, are directly targeting receptors or transporters specific for these three monoamines. Only one vesicular transporter, the vesicular monoamine transporter (VMAT2) is accumulating MA in their specific vesicles, that will be further released from the nerve terminals, to activates the various receptors. Therefore, the VMAT2 controls MA concentration in the terminals, and the intensity of the monoamine release at the synapse. However, because the same VMAT2 is present in all MA terminals, dopamine, serotonin or noradrenalin, it is not possible to study each system separately, and therefore to be able to understand how the control of transmitter fluxes, and the balance between these three MA systems, is possibly involved to regulates brain functions. We have now produced a genetic mouse model allowing, for the first time, the conditional suppression of VMAT2 in specific neuronal subsets, or at specific times during development and adulthood. This model will now allow us, within the next years, to unravel these very important questions, and to have eventually a better understanding of the respective role and circuits of these three intermingled and essential neurotranmitter systems.