Abstract Details

Title L-Dopa-Induced Dyskinesias are Reduced by Propranolol in Parkinsonian Mice

Topic Movement Disorders

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-002

Objective We hypothesized that adrenergic receptors located on striatal acetylcholine-releasing interneurons (ChIs) might regulate acetylcholine availability and alleviate L-Dopa-induced dyskinesias (LIDs).

Background Genetic and acquired forms of Parkinsonism reduces striatal dopamine availability to produce motor dysfunction in children and adults. While L-Dopa can improve function, its use is often limited by LIDs. LIDs occur, in part, through compensatory changes in ChIs, which provide a major source of striatal acetylcholine.

Design/Methods We used behavioral and electrophysiological techniques in a new genetically-modified model of parkinsonism. Dopamine cells in Slc6a3^DTR/+ mice were specifically rendered sensitive to diphtheria toxin, which has little effect on WT mice. The activity of striatal ChIs in vitro was assessed by cell-attached recordings in acute slice preparations, while motor function was assessed by a blinded examiner using the open field, balance beam, and rotarod tests. Chat^Cre x Rosa26-fs-tdTomato mice were used to visualize the sparse population of striatal ChIs by fluorescent microscopy.

Results Treatment of 30-day-old Slc6a3^DTR/+ x Chat^Cre x Rosa26-fs-tdTomato mice with diphtheria toxin (50 µg/kg, i.m.) produced selective ablation of dopamine neurons and a progressive reduction in striatal dopamine (~60%) motor function after 12 days. Subsequent treatment with L-Dopa (25 mg/kg/d, i.p.) combined with the Dopa-decarboxylase inhibitor benserazide (12 mg/kg/d, i.p.) for 10 weeks produced dyskinesias that were then reduced by co-treatment of the beta-adrenergic receptor antagonist propranolol (20 mg/kg/d i.p.). Spontaneous ChI firing decreased with the beta-antagonist propranolol (10 μM) and increased with the beta-agonist isoproterenol (100 nM).

Conclusions

Slc6a3^DTR/+ mice provide a new dopamine-responsive model for progressive parkinsonism, and the data shows that LIDs are reduced by physiologically-relevant concentrations of propranolol. The potential off-target use of propranolol for LIDs requires further investigation.

Authors/Disclosures
Nigel S. Bamford, MD (Yale University) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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