title: Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.
abstract: Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in l-DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Corinne Y
authors: CY
authors: Ostock
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Joy
authors: J
authors: Hallmark
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Noel
authors: N
authors: Palumbo
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Nirmal
authors: N
authors: Bhide
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Melissa
authors: M
authors: Conti
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA.
authors: Jessica A
authors: JA
authors: George
authors: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, USA. Electronic address: cbishop@binghamton.edu.
authors: Christopher
authors: C
authors: Bishop
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000633:toxicity*; D003000:Clonidine / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology* / Q000633:toxicity*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000978:Antiparkinson Agents; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D007980:Levodopa; D016627:Oxidopamine; D003000:Clonidine
keywords: Atipamezole; Clonidine; Locus coeruleus; Norepinephrine; l-DOPA-Induced dyskinesia; α2-adrenoceptor