Abstract
Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as l-DOPA-induced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(±)propranolol], a nonselective β-adrenergic receptor (βAR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (±)propranolol as an adjunct to therapy with l-DOPA. We first determined whether (±)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF l-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (±)propranolol on markers of striatal activity known to be involved in LID. To determine whether (±)propranolol reduces LID through βAR blockade, we subsequently examined each enantiomer separately because only the (−)enantiomer has significant βAR affinity. We next investigated the effects of a localized striatal βAR blockade on LID by cannulating the region and microinfusing (±)propranolol before systemic l-DOPA injections. Results showed that a dose range of (±)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (−)propranolol had anti-LID properties indicating βAR-specific effects. Aberrant striatal signaling associated with LID was normalized with (±)propranolol cotreatment, and intrastriatal (±)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (±)propranolol reduces LID through βAR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS059600]; and the Center for Development and Behavioral Neuroscience at Binghamton University.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179416.
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ABBREVIATIONS:
- DA
- dopamine
- PD
- Parkinson's disease
- l-DOPA
- l-3,4-dihydroxyphenylalanine
- LID
- l-DOPA-induced dyskinesia
- 5-HT
- serotonin
- βAR
- β-adrenergic receptor
- AIMs
- abnormal involuntary movements
- PPD
- preprodynorphin
- PPE
- preproenkephalin
- PPT
- preprotachykinin
- 6-OHDA
- 6-hydroxydopamine
- MFB
- medial forebrain bundle
- ALO
- axial limb and orolingual
- FAS
- forepaw adjusting steps
- VEH
- vehicle
- RT-PCR
- reverse transcription-polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- HPLC-ED
- high-performance liquid chromatography with electrochemical detection
- PRO(1μg)
- 1 μg (±)propranolol
- (±)PRO5
- 5 mg/kg (±)propranolol
- (±)PRO20
- 20 mg/kg (±)propranolol
- (±)PRO40
- 40 mg/kg (±)propranolol
- PRO(10μg)
- 10 μg (±)propranolol
- DARPP-32
- dopamine- and cAMP-regulated phosphoprotein of 32 kDa.
- Received January 14, 2011.
- Accepted March 11, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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