RT Journal Article
SR Electronic
T1 Behavioral and Cellular Modulation of L-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-OHDA-Lesioned Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.179416
DO 10.1124/jpet.111.179416
A1 David Lindenbach
A1 Corinne Y Ostock
A1 Karen L Eskow Jaunarajs
A1 Kristin B Dupre
A1 Christopher J Barnum
A1 Nirmal Bhide
A1 Christopher Bishop
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/03/14/jpet.111.179416.abstract
AB 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.