Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Downs, A. M. R.; Fan, Xionglin; Donsante, Christine; Jinnah, Hyder A.; Hess, Ellen J.

doi:10.1016/j.nbd.2019.01.012

Cited by 30 publications

(21 citation statements)

References 62 publications

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“…Additionally, to our knowledge, there are no data on abnormal muscarinic receptor expression in the caudate putamen of dystonia patients. Finally, our data also supports the recent shift in research focus towards nicotinergic receptors [24], which may in fact facilitate alterations found in dopamine signaling, and thus represent an interesting therapeutic target.…”

Section: Discussionsupporting

confidence: 87%

“…Based on these evidences we expected downregulation of muscarinic receptors in hypercholinergic DYT1 KI mice. The instead observed increase in M1 mRNA originating from presumably dysregulated medium spiny neurons, supports a more complex regulation of cholinergic transmission, likely involving dopamine receptor signaling and converging molecular pathways [24]. It is widely appreciated that transcript and protein levels often do not correlate; however, in summary our data supports that changes in M1R expression are unlikely to underlie the aberrant corticostriatal plasticity with higher long-term potentiation in DYT1 mice normalized by M1-preferring antagonists [25].…”

Section: Resultsmentioning

confidence: 86%

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Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

et al. 2019

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In early-onset generalized torsion dystonia, caused by a GAG deletion in TOR1A (DYT1), enhanced striatal cholinergic activity has been suggested to be critically involved. Previous studies have shown increased acetylcholine levels in the striatum of DYT1 knock-in (KI) mice. Ex vivo data indicated that muscarinic receptor antagonists normalize the activity of striatal cholinergic interneurons. Currently receptor subtype specific antagonists are developed for therapy, however, it is yet unknown whether the levels of targeted receptors are unaltered. In the present study, we firstly examined the expression of M1 and M4 receptors in DYT1 KI mice in comparison to wildtype mice. While no changes in mRNA were found in the motor cortex, the expression of M1 was higher in the striatum of DYT1 KI. However, M1 protein did not differ in striatum and cortex between the animal groups as shown by immunohistochemistry and western blot. M4 receptor protein, unaltered in the cortex, was slightly lower in lateral subparts of the striatum, but unchanged in somata of cholinergic interneurons and substance P immunoreactive projection neurons. Functional alterations of the cholinergic system and of aberrant striatal plasticity, demonstrated by previous studies, seem not to be related to overt changes in M1 and M4 expression. This critically informs the ongoing development of respective antagonists for therapy of dystonia.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 86%

Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

et al. 2019

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“…Some of these genes, such as the genes which are causative for DRD, have clear links to the synthesis, degradation, or signaling of DA 6,29,33 . However, several genetic forms of dystonia, such as Dyt1, have no clear link to DA, although some mouse models of these genetic forms of dystonia do show DA deficits 34,35 . Similar to trihexyphenidyl, which is used clinically to treat movement disorders, VU6021625 reduces abnormal movements in one of these DA-focused models of dystonia.…”

Section: Discussionmentioning

confidence: 99%

“…Data are expressed as mean latency to withdraw + SEM or percent inhibition of catalepsy + SEM. At the end of the study (0.5 hr post-administration of VU6021625), plasma and brain samples from each rat (all dose groups) were collected and stored (-80 ºC) for bioanalysis by LC-MS/MS as described previously 35,[39][40] .…”

Section: Discussionmentioning

confidence: 99%

Discovery of the first selective M₄muscarinic acetylcholine receptor antagonists within vivoanti-parkinsonian and anti-dystonic efficacy

Moehle

Bender

Dickerson

et al. 2020

Preprint

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Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

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“…Fast scan cyclic voltammetry (FSCV) to measure DA release was performed according to previously published methods (Downs et al, 2019). Mice were euthanized using cervical dislocation and 300 μm sections were prepared using a vibratome in ice-cold oxygenated…”

Section: Fast Scan Cyclic Voltammetrymentioning

confidence: 99%

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OFTOR1ADYSTONIA

Downs

Donsante

Jinnah

et al. 2020

Preprint

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Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is the preferred oral pharmaceutical for the treatment of DYT1-TOR1A dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. Using a mouse model of DYT1-TOR1A dystonia (Tor1a+/ΔE KI mice), we recently found that THP normalized striatal DA release, revealing a plausible mechanism of action for this compound. However, the exact mAChR subtypes that mediate this effect remain unclear. In this study we used a combination of a newly developed M4 subtype-selective mAChR antagonist and cell-type specific mAChR KO mice to determine which mAChR subtypes mediate the DA enhancing effects of THP. We determined that THP and the M4 subtype-selective mAChR antagonist enhance striatal DA release by blocking M4 mAChR on striatal cholinergic interneurons in Tor1a+/ΔE KI mice. However, in Tor1a+/+ mice THP increases striatal DA release through a combination of M1 and M4 mAChR, which reveals an alteration in M1 mAChR function in Tor1a+/ΔE KI mice. Taken together these data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that M4-subtype selective mAChR antagonists may be more efficacious therapeutics for DYT1-TOR1A dystonia.SIGNIFICANCE STATEMENTTrihexyphenidyl, a non-selective muscarinic receptor antagonist, is the preferred oral therapeutic for DYT1-TOR1A dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved therapeutics. We recently found that trihexyphenidyl rescues the deficit in both striatal dopamine release and steady-state extracellular striatal dopamine concentrations in a mouse model of DYT1-TOR1A dystonia. However, the precise muscarinic receptor subtype(s) that mediate these effects are unknown. We used a newly developed M4 muscarinic receptor subtype-selective antagonist along with M1 and M4 muscarinic receptor knockout mice to determine the precise muscarinic receptor subtypes that mediate the dopamine-enhancing effects of trihexyphenidyl.

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Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Cited by 30 publications

References 62 publications

Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

Discovery of the first selective M₄muscarinic acetylcholine receptor antagonists within vivoanti-parkinsonian and anti-dystonic efficacy

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OFTOR1ADYSTONIA

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Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Cited by 30 publications

References 62 publications

Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

Subtle changes in striatal muscarinic M1 and M4 receptor expression in the DYT1 knock-in mouse model of dystonia

Discovery of the first selective M4muscarinic acetylcholine receptor antagonists within vivoanti-parkinsonian and anti-dystonic efficacy

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OFTOR1ADYSTONIA

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Discovery of the first selective M₄muscarinic acetylcholine receptor antagonists within vivoanti-parkinsonian and anti-dystonic efficacy