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The inhibition of vesicular monoamine transporter 2 partially reduces the toxicity of 6-hydroxydopamine on nigro-striatal dopamine neurons

The inhibition of vesicular monoamine transporter 2 partially reduces the toxicity of 6-hydroxydopamine on nigro-striatal dopamine neurons

Society for Neuroscience Abstracts 27(1): 1148

In monoaminergic neurons of the central nervous system, the vesicular monoamine transporter 2 (VMAT2) ensures storage of monoamines into synaptic vesicles. Moreover, these vesicles are able to sequestrate neurotoxins, such as MPP+, and thereby prevent their neurotoxic action. We wanted to know whether the well documented toxic effects displayed by 6OHDA on the nigro-striatal dopamine neurons were modified by the inhibition of VMAT2, operated by its reversible inhibitor tetrabenazine (TBZ). Male Swiss albino mice were pretreated s.c. with TBZ (30 mg/kg); 90 min later, when hypothermia is well established, an intracerebroventricular injection of 6OHDA (50 mug/10mul) was operated. Mice were sacrificed 8 days later. A membrane fraction prepared from striatal synaptosomes was used to determine the (3H)dihydrotetrabenazine binding in order to evaluate the striatal VMAT2 density, which constitutes an index of the striatal dopaminergic innervation. Pretreatment with TBZ in control mice did not alter significantly the (3H)dihydrotetrabenazine binding. 6OHDA induced a major and significant decrease (-50%; p<0.001) in VMAT2 density in vehicle pretreated mice, whereas in TBZ pretreated mice a partial protection was observed, since the decrease induced by 6OHDA was weaker but significant (-20%; p<0.05) compared to TBZ control group. Thus, unexpectedly, it appears that whereas the vesicular MPP+ uptake protects from its neurotoxic effect, that of 6OHDA would lead to a worsening of its neurotoxicity.

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