Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants.

Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also demonstrated rescue of nine VMAT2 variants that cause Brain Monoamine Vesicular Transport Disease (BMVTD). VMAT2 upregulation could be beneficial for disorders associated with reduced monoamine transmission, including mood disorders and BMVTD, a rare but often fatal condition caused by a lack of functional VMAT2. Our findings provide the first evidence that small molecules can upregulate VMAT2 and have potential therapeutic benefit for various neuropsychiatric conditions.

Neurotoxicology of dopamine: Victim or assailant?

Since the identification of dopamine as a neurotransmitter in the mid-20th century, investigators have examined the regulation of dopamine homeostasis at a basic biological level and in human disorders. Genetic animal models that manipulate the expression of proteins involved in dopamine homeostasis have provided key insight into the consequences of dysregulated dopamine. As a result, we have come to understand the potential of dopamine to act as an endogenous neurotoxin through the generation of reactive oxygen species and reactive metabolites that can damage cellular macromolecules. Endogenous factors, such as genetic variation and subcellular processes, and exogenous factors, such as environmental exposures, have been identified as contributors to the dysregulation of dopamine homeostasis. Given the variety of dysregulating factors that impact dopamine homeostasis and the potential for dopamine itself to contribute to further cellular dysfunction, dopamine can be viewed as both the victim and an assailant of neurotoxicity. Parkinson's disease has emerged as the exemplar case study of dopamine dysregulation due to the genetic and environmental factors known to contribute to disease risk, and due to the evidence of dysregulated dopamine as a pathologic and pathogenic feature of the disease. This review, inspired by the talk, "Dopamine in Durham: location, location, location" presented by Dr. Miller for the Jacob Hooisma Memorial Lecture at the International Neurotoxicology Association meeting in 2023, offers a primer on dopamine toxicity covering endogenous and exogenous factors that disrupt dopamine homeostasis and the actions of dopamine as an endogenous neurotoxin.

Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity.

Dopaminergic neurons of the substantia nigra exist in a persistent state of vulnerability resulting from high baseline oxidative stress, high-energy demand, and broad unmyelinated axonal arborisations. Impairments in the storage of dopamine compound this stress because of cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Parkinson's disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously published in vitro assay utilising false fluorescent neurotransmitter 206 (FFN206) to visualise how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopamine in the vesicular compartment with radiolabelled dopamine in vesicles isolated from immortalised cells and from mouse brain. Further, we demonstrate that SV2C enhances the ability of vesicles to store the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants and helps maintain the integrity of dopaminergic neurons.