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

• Type of Material: Article
• Authors: Anthony M. Downs, Emory University; Xueliang Fan, Emory University; Christine Donsante, Emory University; Hyder Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2019-05-01
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019 ELSEVIER
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2019.01.012
• Title of Journal or Parent Work: NEUROBIOLOGY OF DISEASE
• Volume: 125
• Start Page: 115
• End Page: 122
• Grant/Funding Information: This work was supported by United States Department of Defense grant W81XWH-15-1-0545 and United States National Institute of Health Grants F31 NS103363 and T32 GM008602.
• Keywords: Life Sciences & Biomedicine; PROJECTION NEURONS; Science & Technology; CHOLINERGIC INTERNEURONS; Neurosciences & Neurology; Neurosciences; RELEASE; PRESYNAPTIC NICOTINIC RECEPTORS; Fast scan cyclic voltammetry; TRANSMISSION; SYNAPTIC PLASTICITY; Nicotinic; STRIATAL DOPAMINE; Microdialysis; BINDING; Muscarinic; Acetylcholine; TORSION DYSTONIA; DORSAL
• Research Categories: Health Sciences, Public Health; Biology, Neuroscience; Health Sciences, Toxicology

Abstract

Trihexyphenidyl, a nonselective muscarinic receptor antagonist, is the small molecule drug of choice for the treatment of DYT1 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 treatments. Because DTY1 dystonia is associated with both abnormal cholinergic neurotransmission and abnormal dopamine regulation, we tested the hypothesis that trihexyphenidyl normalizes striatal dopamine release in a mouse model of DYT1 dystonia using ex vivo fast scan cyclic voltammetry and in vivo microdialysis. Trihexyphenidyl increased striatal dopamine release and efflux as assessed by ex vivo voltammetry and in vivo microdialysis respectively. In contrast, ʟ-DOPA, which is not usually effective for the treatment of DYT1 dystonia, did not increase dopamine release in either Dyt1 or control mice. Trihexyphenidyl was less effective at enhancing dopamine release in Dyt1 mice relative to controls ex vivo (mean increase WT: 65% vs Dyt1: 35%). Trihexyphenidyl required nicotinic receptors but not glutamate receptors to increase dopamine release. Dyt1 mice were more sensitive to the dopamine release decreasing effects of nicotinic acetylcholine receptor antagonism (IC 50 : WT = 29.46 nM, Dyt1 = 12.26 nM) and less sensitive to acetylcholinesterase inhibitors suggesting that nicotinic acetylcholine receptor neurotransmission is altered in Dyt1 mice, that nicotinic receptors indirectly mediate the differential effects of trihexyphenidyl in Dyt1 mice, and that nicotinic receptors may be suitable therapeutic targets for DYT1 dystonia.