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Exocytosis of Nonclassical Neurotransmitters
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Xiao Su, Vincent R. Mirabella, Kenneth G. Paradiso, Zhiping P. Pang
Different from fast transmitters that form classical point-to-point transmission, dopamine was suggested to be released via a volume transmission mode, where neuromodulators diffuse to mediate effects in many cells over a large area or a longer distance (Agnati et al., 1995; Caille et al., 1996; Liu et al., 2018). Dopamine can also be released from soma and dendrites (Geffen et al., 1976). A large amount of morphological and functional evidence including immunohistochemistry, amperometry, and whole-cell voltage clamp support the belief that most of dopamine transmission is mediated by vesicular exocytosis (Caille et al., 1996; Kress et al., 2014; Staal et al., 2004; Uchigashima et al., 2016; Yung et al., 1995). The ablation of vesicular monoamine transporter type 2 (VMAT2) which is a major vesicular transporter for dopamine eliminates dopamine transmission (Fon et al., 1997). Here, we mainly focus on axonal dopamine release and related machinery involved in dopamine secretion.
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Common to all monoaminergic neurotransmitters are reuptake mechanisms in which the released neurotransmitter is taken back into the secreting cell by membrane-embedded transporters. Reuptake fulfills two important functions: (1) guarding against neuronal overstimulation through the removal of the released messenger from the synaptic cleft, resulting in the rapid termination of its actions, and (2) enabling energy conservation by recycling and reutilizing existing molecules rather than producing energy-costly new transmitters [37]. Once the released molecule is brought back into the secreting cell, the next step is its repackaging into storage/secretory vesicles (Figure 1.6). Repackaging is accomplished by two vesicular monoamine transporters, VMAT1 and VMAT2, whose main roles are to (1) protect the transmitter from degradation by intracellular MAO, (2) maintain an adequate intraneuronal storage/secretory capacity to ensure prompt responses to subsequent stimuli, and (3) enable a regulated release of the neurotransmitter from storage vesicles rather than its unregulated release by diffusion [38].
Adrenergic Agonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
VMAT, a VNT, prevents leakage and deterioration of the neurotransmitters thereby maintaining a check in its concentration within the cytoplasm. These are of two types VMAT-1 and VMAT-2. VMAT-1 is located in the peripheral organs particularly the cells of the paracrine and endocrine glands whereas VMAT-2 is located in the vesicular transporter located in CNS, histaminergic cells of adrenal medulla, blood cells, and stomach (Mahata et al., 1993; Peter et al., 1995; Weihe et al., 1994; Erickson et al., 1996). Reserpine blocks both VMAT-1 as well as VMAT-2 leading to reduced uptake of dopamine as well as noradrenaline into the synaptic vesicles leading to its degradation by MAO thereby inhibiting adrenergic neurotransmission at the synapses. Apart from reserpine, tetrabenazine and methamphetamine also have competitive blocking action on VMAT-2, which is more sensitive compared to VMAT-1 (Erickson et al., 1996; Peter et al., 1994). The enhancement of storage of neurotransmitters like dopamine and noradrenaline can be a good remedy in the discipline of psychiatry and in behavioral, locomotory defective disorders like parkinsonism.
VMAT2 Inhibitors for the Treatment of Tardive Dyskinesia
Published in Issues in Mental Health Nursing, 2022
Barbara Warren, Dawn Vanderhoef, Jessica Johnson
The pathophysiology of TD is not well understood, but it has been hypothesized that prolonged blockade of postsynaptic dopamine receptors may lead to dopaminergic hypersensitivity that results in hyperkinetic movements (Waln & Jankovic, 2013). VMAT2 transporters are primarily located on presynaptic vesicles in the central nervous system and play a crucial role in the packaging and release of dopamine and other monoamines into the neuronal synapse (Harriott et al., 2018). By reducing the packaging and subsequent release of dopamine from presynaptic vesicles, VMAT2 inhibitors are believed to counteract the unwanted effects of prolonged antipsychotic exposure on motor function. Other theories, including a disturbance of GABA and glutamate balance, oxidative stress, and damage to cholinergic interneurons, have led to off-label use of various agents, with minimal or limited efficacy in the treatment of TD (see below section: Current Treatment Recommendations for TD) (Bhidayasiri et al., 2013; 2018; Waln & Jankovic, 2013).
State-of-the-art pharmacological approaches to reduce chorea in Huntington’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
Jessie S. Gibson, Daniel O. Claassen
Another outstanding question relates to timing of antichoreatic medication initiation. It is unclear whether antipsychotics or VMAT-2 inhibitors have disease-modifying effects over time, though it is theoretically possible that earlier use of VMAT-2 inhibitors could prevent D2 receptor upregulation and reduce chorea burden as the HD progresses. On the other hand, early use of risperidone, with strong D2 affinity, could lead to faster progression of dystonia and bradykinetic features of HD. Longitudinal comparative effectiveness studies could help answer these outstanding questions as they pertain to real-world HD patients, with consideration for comorbidities requiring treatment (e.g. psychiatric symptoms) or modifying treatment (e.g. anosognosia or dysphagia leading to noncompliance) as well as individual medication histories and financial limitations.
Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia
Published in Expert Review of Neurotherapeutics, 2021
Benjamin J. Dorfman, Joohi Jimenez-Shahed
Treatment strategies for TD include cessation of the offending DRBA, increasing doses of the DRBA, botulinum toxin injections for amenable movements, and use of VMAT2 inhibitors [9]. VMAT2 is a vesicular membrane protein present in both central and peripheral neurons that transports monoamines, including dopamine, into vesicles inside presynaptic neurons for eventual release into the synaptic cleft [29]. Inhibition of VMAT2 prevents this process, leaving unpackaged monoamines remaining in the cytosol to be broken down by monoamine oxidase (MAO), thus depleting presynaptic monoamine stores. Clinically significant doses of VMAT2 inhibitors preferentially affect dopamine over other monoamines, making them a particularly relevant option for the management of hyperkinetic movements. Importantly, VMAT2 inhibitors have a different site of action than DRBAs, and hence do not share the risk of causing TS. A comparison of currently available VMAT2 inhibitors may be found in Table 1.