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Reducing Dopamine Leads to Less “Go” and More “Stop” from the Motor Striatum for Robust Therapeutic Effects Stephen M

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Reducing Dopamine Leads to Less “Go” and More “Stop” from the Motor Striatum for Robust Therapeutic Effects Stephen M CNS Spectrums (2018), 23,1–6. © Cambridge University Press 2017 doi:10.1017/S1092852917000621 First published online 18 December 2017 BRAINSTORMS—Clinical Neuroscience Update Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less “go” and more “stop” from the motor striatum for robust therapeutic effects Stephen M. Stahl ISSUE: Tardive dyskinesia can now be successfully treated by inhibiting the vesicular monoamine transporter type 2 (VMAT2). for the significance of this new breakthrough treatment Take-Home Points mechanism. ’ Inhibition of the vesicular monoamine transporter type 2 (VMAT2) reduces dopamine storage and VMAT2 and Its Inhibition by Tetrabenazine release. Transporters for neurotransmitters exist not only on ’ Diminishing dopamine release in turn curtails the presynaptic nerve terminals (the well-known “reuptake hypothetical overstimulation of supersensitive D2 dopamine pumps” targeted by most drugs for depression), but also receptors in the motor striatum that causes tardive on synaptic vesicles.3 Several types of vesicular transpor- dyskinesia. ters have been identified, including different ones for gamma amino butyric acid (GABA), glutamate, glycine, ’ Trimming dopamine release via VMAT2 inhibition in the acetylcholine, monoamines, and others.3 The specific motor striatum results in stronger “stop” signals and transporter known as VMAT2 is located on synaptic weaker “go,” signals and thus robust therapeutic effects vesicles of dopamine, norepinephrine, serotonin, and in reducing the abnormal involuntary hyperkinetic histamine neurons to store these neurotransmitters until movements of tardive dyskinesia. – needed for release during neurotransmission.3 7 VMAT2 can also transport certain drugs as “false” substrates, such as amphetamine and ecstasy (MDMA; 3,4-methyle- Introduction nedioxymethamphetamine), which can compete for the “true,” natural neurotransmitter.3 Synaptic vesicles create Until recently, therapeutic options for tardive dyskine- low pH in their lumens (interiors) with an energy- sia (TD) were few and unsatisfactory. The introduction requiring proton pump there.3,6 LowpHinturnservesas of drugs with a new mechanism of action, namely the driving force to sequester the neurotransmitter in the inhibition of the vesicular monoamine transporter synaptic vesicle.3,6 type 2 (VMAT2), is now transforming the treat- There are actually two types of VMATs: VMAT1, ment of TD.1,2 Here we review dopamine neuro- which is localized in both the peripheral and central – transmission (see also References3 8) and how it is nervous system (CNS), and VMAT2, located only in the – affected by TD and by various drugs to set the stage CNS.3 7 There are two known VMAT inhibitors: Downloaded from https://www.cambridge.org/core. IP address: 170.106.202.126, on 27 Sep 2021 at 10:58:42, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000621 2 S. M. Stahl BRAINSTORMS—Clinical Neuroscience Update Figure 1. Tardive dyskinesia as imbalance in “stop” and “go” signals from the motor striatum. D2 receptors in the indirect pathway of the motor striatum hypothetically react to chronic blockade by D2 antagonists by “learning” to have tardive dyskinesia with aberrant neuronal plasticity, resulting in supersensitivity to dopamine. This leads to too much inhibition of “stop” signals coming from too much dopamine acting at upregulated D2 receptors in the indirect pathway (on the right), and unopposed “go” signals coming from the direct pathway (on the left), and thus involuntary hyperkinetic movements. Tardive Dyskinesia : Supersensitive D2 Receptors = D1 overstimulation of supersensitive = D2 upregulated D2 receptors D2 stimulated = VMAT2 GABA neuron = D2 blocker glu D1 stimulated normal DA neurotransmission glutamate GABA neurotransmission neuron blocked D2 receptors direct indirect pathway pathway go stop DA DA too much inhibition of “stop” GO net striatal output: too much “go” in motor pathways and thus tardive dyskinesia reserpine, which inhibits irreversibly both VMAT1 and slowly; valbenazine is converted only into the alpha- VMAT2, and tetrabenazine, which reversibly inhibits hydroxy metabolite.1,2,7 only VMAT2. That is why reserpine-related drugs, but not tetrabenazine-related drugs, are associated with frequent peripheral side effects, such as orthostatic Treating Overstimulation of D2 Receptors in hypotension (reserpine was once used for hyperten- Tardive Dyskinesia sion), stuffy nose, itching, and gastrointestinal side effects. Although VMAT2 transports multiple neuro- D2 receptors in the indirect pathway of the motor transmitters into synaptic vesicles, tetrabenazine pre- striatum hypothetically react to chronic blockade by D2 ferentially affects dopamine at clinical doses.7 When antagonists by “learning” to have tardive dyskinesia tetrabenazine blocks the transport of dopamine into with aberrant neuronal plasticity, resulting in super- presynaptic vesicles, dopamine is rapidly degraded by sensitivity to dopamine.4 This leads to too much monoamine oxidase (MAO), leading to depletion of inhibition of “stop” signals coming from too much presynaptic dopamine proportionate to the degree of dopamine acting at upregulated D2 receptors in the VMAT2 inhibition.3 Tetrabenazine itself is rapidly indirect pathway (Figure 1 on the right) and unopposed absorbed and converted into active metabolites, espe- “go” signals coming from the direct pathway (Figure 1 cially alpha and beta hydroxytetrabenazine.7 Deuter- on the left), and thus involuntary hyperkinetic move- ated tetrabenazine is similarly metabolized, but more ments.4 If the brain has literally “learned” to have TD in Downloaded from https://www.cambridge.org/core. IP address: 170.106.202.126, on 27 Sep 2021 at 10:58:42, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000621 Mechanism of action of vesicular monoamine transporter 3 BRAINSTORMS—Clinical Neuroscience Update Figure 2. Raising the dose of D2 blockers in tardive dyskinesia. In an attempt to suppress unwanted hyperkinetic movements of TD, one can try to raise the dose of D2 antagonist to block some of those upregulated supersensitive D2 receptors. This might work short term in some patients but at the expense of more immediate side effects and the prospects of making TD even worse long term. Raising the Dose of D2 Blocker in Tardive Dyskinesia = D1 more D2 blockade due to less D2 stimulation due to = D2 increased dose of antipsychotic more D2 blockade = VMAT2 GABA neuron = D2 blocker glu D1 stimulated normal DA neurotransmission GABA glutamate neurotransmission neuron direct indirect pathway pathway go stop DA DA less inhibition of “stop” due to increased dose of antipsychotic GO more “stop” results in less tardive dyskinesia short term an aberrant attempt to compensate for chronic D2 their movements—will enjoy reversal of their TD.9 In blockade that results in dopamine overstimulation, fact, most patients experience an immediate worsening then TD would seem to be a disorder ideally set up of their movements when D2 blockade is eliminated, to respond to interventions that lower dopamine due to the completely unblocked actions of dopamine neurotransmission. How can this be done? in the absence of any D2 antagonist therapy at all One way is to raise the dose of D2 antagonist to block (Figure 3). those upregulated supersensitive D2 receptors VMAT2 inhibition is a mechanism that reduces (Figure 2). This might work in the short term in some dopamine stimulation without blocking D2 receptors. patients at the expense of more immediate side effects Thus, this action reduces the overstimulation of D2 and the prospects of making TD even worse down the receptors in the indirect pathway (on the right in road.9 Another treatment possibility is to stop the Figure 4), resulting in less inhibition of the stop signal offending D2 antagonist with the hope that the motor there. However, there is also a benefit of VMAT2 system will re-adjust back to normal and the movement inhibition in the direct pathway where “go” signals are disorder will reverse (Figure 3). Indeed, many patients amplified by dopamine at D1 receptors.4,5 Even though who do not have an underlying psychotic disorder may these D1 receptors and this direct extrapyramidal be able to tolerate the discontinuation of their D2 pathway may not be the site of pathology in TD,4 they antagonist. Unfortunately, it does not seem that the TD do drive “go” signals for movement,6 and lowering brain can “forget” its aberrant neuroplastic learning dopamine there by VMAT2 inhibition would thus be very well, and only some patients—particularly those expected to lower the “go” signals arising from the who discontinue D2 blockade soon after the onset of direct pathway (Figure 4 on the left).4 Combined with Downloaded from https://www.cambridge.org/core. IP address: 170.106.202.126, on 27 Sep 2021 at 10:58:42, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000621 4 S. M. Stahl BRAINSTORMS—Clinical Neuroscience Update Figure 3. Discontinuing D2 blockers in tardive dyskinesia. Sometimes it is necessary or desirable to discontinue the D2 antagonist causing TD in the hope that the motor system will re-adjust back to normal and the movement disorder will reverse. Sometimes the underlying
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