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  • Title: Behavioral and cellular modulation of L-DOPA-induced dyskinesia by beta-adrenoceptor blockade in the 6-hydroxydopamine-lesioned rat.
    Author: Lindenbach D, Ostock CY, Eskow Jaunarajs KL, Dupre KB, Barnum CJ, Bhide N, Bishop C.
    Journal: J Pharmacol Exp Ther; 2011 Jun; 337(3):755-65. PubMed ID: 21402691.
    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.
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