Nicotinic Receptor Dysfunction Underlies Abnormal Responses to Muscarinic Receptor Antagonist Treatment in DYT1 Dystonia

Abstract

DYT1 dystonia is an inherited dystonia caused by a mutation in the TOR1A gene, which encodes the torsinA protein. Trihexyphenidyl (THP) 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 both the underlying pathology of DYT1 dystonia and the mechanism of action of THP is needed for the development of better treatments. Abnormalities in dopamine (DA) transmission have been implicated in DYT1 and other forms of dystonia. Previous studies have shown that Dyt1 knockin mice have reduced extracellular striatal DA in vivo and reduced striatal DA release ex vivo. Acetylcholine (ACh) is known to play a key role in regulating striatal DA release, and muscarinic receptor antagonists are used to treat dystonia which suggests the hypothesis that ACh signaling mediates the DA release deficiency in DYT1 dystonia. To test this hypothesis, we used ex vivo fast scan cyclic voltammetry (FSCV) and in vivo microdialysis to investigate ACh regulation of striatal DA release in Dyt1 knockin mice. We found that THP increased striatal DA release as assessed by ex vivo FSCV and in vivo microdialysis. However, THP was less effective at enhancing DA release in DYT1 mice relative to WT mice in the ex vivo FSCV experiment (mean increase WT: 65% vs DYT1: 35%). In striatum, blocking mACh autoreceptors on cholinergic interneurons increases ACh release. ACh then activates nicotinic acetylcholine receptors (nAChRs) located on DA terminals to enhance DA release. To determine if abnormal nAChR responses could account for the attenuated response to THP in Dyt1 knockin mice, we performed a dose response experiment with the α4 nAChR subunit selective antagonist dihydro‐β‐erythroidine. We found that Dyt1 mice are more sensitive to nAChR antagonism, which reduces DA release (IC50: WT= 29.46nM, DYT1= 12.26nM). These data suggest that nAChRs mediate the differential effects of THP in Dyt1 mice. These data also suggest that nAChRs may be suitable therapeutic targets for DYT1 dystonia. Future studies will evaluate nAChR positive allosteric modulators for DA‐enhancing effects.Support or Funding InformationSupported by: DoD W81XWH‐15‐1‐0545 and NIH T32‐GM008602This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.