Chronic dopamine (DA) replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-3,4,-dihydroxyphenylalanine (L-DOPA)-induced dysinesias (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-Isopropylamino-3-(1-naphthyloxy)-2-propanol ((±)propranolol), a non-selective β-adrenergic receptor (βAR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD to characterize and localize the efficacy of (±)propranolol as an adjunct to therapy with L-DOPA. We first determined if (±)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 RT-PCR techniques to analyze the effects of chronic (±)propranolol on markers of striatal activity known to be involved in LID. In order to determine whether (±)propranolol reduces LID through βAR blockade, we subsequently examined each enantiomer separately since only the (-) enantiomer has significant βAR affinity. Next, we investigated the effects of a localized striatal βAR blockade on LID by cannulating the region and microinfusing (±)propranolol prior to 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 co-treatment 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.
- Received January 14, 2011.
- Revision received March 11, 2011.
- Accepted March 11, 2011.
- The American Society for Pharmacology and Experimental Therapeutics