DYT1 dystonia is an early-onset,
hyperkinetic movement disorder caused by a deletion in the gene TOR1A, which encodes the
protein torsinA. Several lines of evidence show that in animal models of DTY1
dystonia, there is impaired basal
dopamine (DA) release and enhanced
acetylcholine tone. Clinically,
anticholinergic drugs are the most effective pharmacological treatment for
DYT1 dystonia, but the currently used agents are non-selective
muscarinic antagonists and associated with side effects. We used a
DYT1 ∆GAG knock-in mouse model (
DYT1 KI) to investigate whether
nicotine and/or a non-desensitizing
nicotinic agonist,
AZD1446, would increase DA output in
DYT1 dystonia. Using in vivo microdialysis, we found that
DYT1 KI mice showed significantly increased DA output and greater sensitivity to
nicotine compared to wild type (WT) littermate controls. In contrast, neither systemic injection (0.25-0.75 mg/kg) or intrastriatal infusion (30 μM-1 mM) of
AZD1446 had a significant effect on DA efflux in WT or
DYT1 KI mice. In vitro, we found that
AZD1446 had no effect on the membrane properties of striatal spiny projection neurons (SPNs) and did not alter the spontaneous firing of ChI interneurons in either WT or
DYT1 KI mice. We did observe that the firing frequency of dopaminergic neurons was significantly increased by
AZD1446 (10 μM), an effect blocked by
dihydro-beta-erythroidine (DHβE 3 μM), but the effect was similar in WT and
DYT1 KI mice. Our results support the view that
DYT1 models are associated with abnormal striatal
cholinergic transmission, and that the
DYT1 KI animals have enhanced sensitivity to
nicotine. We found little effect of
AZD1446 in this model, suggesting that other approaches to nicotinic modulation should be explored.