MASS SPECTROMETRY IMAGING UNCOVERS SPECIES-SPECIFIC DOPAMINERGIC EFFECTS OF TETRABENAZINE IN RODENTS

Tetrabenazine (TBZ) is a known inhibitor of the vesicular monoamine transporter 2 (VMAT2), resulting in reduced monoaminergic signaling, including dopamine.
Internal behavioral studies have shown that TBZ produces stronger effects on motivational behavior in rats than in mice; however, the neurochemical mechanisms underlying these species-specific differences remain unclear.
This study investigated the impact of TBZ on dopamine transmission in rats and mice using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), a technique that enables high-resolution quantification of neurotransmitters in brain sections.
The main objective was to assess TBZ-induced changes in dopamine levels across species (Wistar rats; C57BL/6 mice) and doses (rats: 0.25, 0.75, 1.5 mg/kg i.p.; mice: 2.5, 5, 10 mg/kg i.p.), with a focus on monoamine depletion and the translational relevance of TBZ. To address species-specific responses, higher TBZ doses were tested in mice, and baseline dopamine levels were directly compared between the two species. Using MALDI‑MSI with FMP‑10 derivatization, striatal and nucleus accumbens sections from both species were analyzed following TBZ or vehicle treatment.
In rats, TBZ produced a linear, dose-dependent reduction in dopamine levels. In contrast, mice exhibited a non-linear response in both the striatum and nucleus accumbens. Moreover, baseline dopamine levels in mouse dorsal striatum were 1.74-fold higher than in rats.
These findings reveal pronounced species-specific differences in both basal dopamine content and neurochemical sensitivity to VMAT2 inhibition. The combined MALDI-MSI and FMP-10 workflow enabled precise mapping of neurotransmitters and underscores the importance of considering species-dependent neurochemistry when interpreting preclinical models of dopaminergic function.