Category: Neuropharmacology
Objective: To evaluate the effects of reversible VMAT2 inhibitors (deutetrabenazine, tetrabenazine and valbenazine) on extracellular levels of monoamines and their acidic metabolites in rat striatum and medial prefrontal cortex (mPFC).
Background: Deutetrabenazine is a selective deuterium-substituted vesicular monoamine transporter-2 (VMAT2) inhibitor, with a similar structure to tetrabenazine. Deutetrabenazine is approved for the treatment of chorea in Huntington’s disease and tardive dyskinesia in adults. VMAT2 is located within and spanning the membranes of synaptic vesicles in monoaminergic neurons. By inhibiting VMAT2, the uptake of monoamines (dopamine DA; serotonin, 5-HT; norepinephrine, NE and histamine) into the synaptic vesicles is attenuated, which results in decreased monoaminergic neurotransmission and enhanced metabolism.
Method: Dual-probe in vivo microdialysis and simultaneous blood sampling experiments were carried out in awake rats (n = 7) following a single administration of 5 mg/kg p.o. of each VMAT2 inhibitor (deutetrabenazine, tetrabenazine and valbenazine). The extracellular levels of monoamines and their metabolites DOPAC, HVA and 5-HIAA were quantified by UHPLC-MS/MS following derivatization with benzoyl chloride. The stereoisomeric pairs of active metabolites of administered parent drugs were separated by chiral column LC-MS/MS and measured in brain microdialysates and in plasma.
Results: A single administration of deutetrabenazine, tetrabenazine or valbenazine, each at a dose of 5 mg/kg p.o. in awake rats caused long-lasting decreases (up to 6 h) in levels of DA and 5-HT (but not NE) in the striatum, and DA and NE (but not 5-HT) in the mPFC. Depletion was most profound for DA in the striatum and NE in the mPFC. The time of maximal DA depletion was in correlation with the time of maximal brain concentrations of the active metabolites. On the other hand, the metabolites DOPAC, HVA and, to a lesser extent, 5-HIAA increased in both brain structures indicating an increase in the monoamine turnover. Finally, the VMAT2 inhibitors did not deplete histamine levels.
Conclusion: The present study confirmed the effects of deutetrabenazine on monoamine depletion and metabolism in vivo. Additionally, our results indicate that all VMAT2 inhibitors tested showed a similar depletion profile in both the striatum and the mPFC.
References: 1. Grigoridadis DE, Smith E, Hoare SRJ, Madan A, Bozigian H. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. J Pharmacol Exp Ther. 2017; 361:454-461. 2. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): A double-blind randomized placebo-controlled phase 3 trial. Lancet Psychiat. 2017;4(8):595-604.
To cite this abstract in AMA style:
E. Adler, L. Magid, O. Even-Chen, S. Schmidt, I. Cope, J. Alexander, J. Kehr, A. Orbach. The effects of acute administration of VMAT2 inhibitors on extracellular levels of dopamine, norepinephrine, 5-HT and histamine in the striatum and medial prefrontal cortex [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/the-effects-of-acute-administration-of-vmat2-inhibitors-on-extracellular-levels-of-dopamine-norepinephrine-5-ht-and-histamine-in-the-striatum-and-medial-prefrontal-cortex/. Accessed November 21, 2024.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-effects-of-acute-administration-of-vmat2-inhibitors-on-extracellular-levels-of-dopamine-norepinephrine-5-ht-and-histamine-in-the-striatum-and-medial-prefrontal-cortex/