Effects of noradrenergic denervation on L-DOPA-induced dyskinesia and its treatment by α- and β-adrenergic receptor antagonists in hemiparkinsonian rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2012-01, Vol.100 (3), p.607-615
• Main Authors: Barnum, Christopher J., Bhide, Nirmal, Lindenbach, David, Surrena, Margaret A., Goldenberg, Adam A., Tignor, Stefanie, Klioueva, Anna, Walters, Hannah, Bishop, Christopher
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-Antagonists - therapeutic use; Adrenergic beta-Antagonists - therapeutic use; Adrenergic Neurons - drug effects; Adult and adolescent clinical studies; Alpha-adrenergic; Animals; Behavior, Animal - drug effects; Beta-adrenergic; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - physiopathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Desipramine - pharmacology; Disease Models, Animal; Dyskinesia; Dyskinesia, Drug-Induced - drug therapy; Dyskinesia, Drug-Induced - physiopathology; Hippocampus - drug effects; Hippocampus - physiopathology; Idazoxan - therapeutic use; L-DOPA; Levodopa - adverse effects; Levodopa - therapeutic use; Male; Medical sciences; Molecular Targeted Therapy; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neuroprotective Agents - pharmacology; Norepinephrine; Organic mental disorders. Neuropsychology; Oxidopamine; Parkinson Disease - drug therapy; Parkinson Disease - physiopathology; Parkinson's disease; Propranolol - therapeutic use; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Sympathectomy, Chemical
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2011.09.009

While L-3,4-dihydroxyphenylalanine (L-DOPA) remains the standard treatment for Parkinson's disease (PD), long-term efficacy is often compromised by L-DOPA-induced dyskinesia (LID). Recent research suggests that targeting the noradrenergic (NE) system may provide relief from both PD and LID, however, most PD patients exhibit NE loss which may modify response to such strategies. Therefore this investigation aimed to characterize the development and expression of LID and the anti-dyskinetic potential of the α2- and β-adrenergic receptor antagonists idazoxan and propranolol, respectively, in rats receiving 6-OHDA lesions with (DA lesion) or without desipramaine protection (DA+NE lesion). Male Sprague–Dawley rats (N=110) received unilateral 6-hydroxydopamine lesions. Fifty-three rats received desipramine to protect NE neurons (DA lesion) and 57 received no desipramine reducing striatal and hippocampal NE content 64% and 86% respectively. In experiment 1, the development and expression of L-DOPA-induced abnormal involuntary movements (AIMs) and rotations were examined. L-DOPA efficacy using the forepaw adjusting steps (FAS) test was also assessed in DA- and DA+NE-lesioned rats. In experiment 2, DA- and DA+NE-lesioned rats received pre-treatments of idazoxan or propranolol followed by L-DOPA after which the effects of these adrenergic compounds were observed. Results demonstrated that moderate NE loss reduced the development and expression of AIMs and rotations but not L-DOPA efficacy while anti-dyskinetic efficacy of α2- and β-adrenergic receptor blockade was maintained. These findings suggest that the NE system modulates LID and support the continued investigation of adrenergic compounds for the improved treatment of PD. ► Moderate NE loss reduces L-DOPA-induced dyskinesia and rotations. ► The α2-adrenergic antagonist idazoxan attenuates L-DOPA-induced dyskinesia. ► Propranolol, a b-adrenergic antagonist, reduces L-DOPA-induced dyskinesia. ► NE lesions do not alter anti-dyskinetic effects of adrenergic receptor antagonists.