Behavioral and Cellular Modulation of L-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

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 beta-adrenergic receptor (beta AR) 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 beta AR blockade, we subsequently examined each enantiomer separately because only the (-)enantiomer has significant beta AR affinity. We next investigated the effects of a localized striatal beta AR 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 beta AR-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 beta AR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.