title: Behavioral and cellular modulation of L-DOPA-induced dyskinesia by beta-adrenoceptor blockade in the 6-hydroxydopamine-lesioned rat.
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.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, P.O. Box 6000, Binghamton, NY 13902-6000, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lindenbach
authors.forename: Corinne Y
authors.initials: CY
authors.lastname: Ostock
authors.forename: Karen L
authors.initials: KL
authors.lastname: Eskow Jaunarajs
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Dupre
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barnum
authors.forename: Nirmal
authors.initials: N
authors.lastname: Bhide
authors.forename: Christopher
authors.initials: C
authors.lastname: Bishop
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D048588:Benzoxazines; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects*; D010078:Oxazines; D016627:Oxidopamine / Q000008:administration & dosage; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D000978:Antiparkinson Agents; D048588:Benzoxazines; D010078:Oxazines; D011943:Receptors, Adrenergic, beta; C028911:cresyl violet; D007980:Levodopa; D016627:Oxidopamine