Behavioral and Cellular Modulation of L-DOPA-Induced Dyskinesia by -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-DOPAinduced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [( )propranolol], a nonselective -adrenergic receptor ( 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 AR blockade, we subsequently examined each enantiomer separately because only the ( )enantiomer has significant AR affinity. We next investigated the effects of a localized striatal 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 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 AR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.