Modulation of L-DOPA’s antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus
| Autor: | Joy Hallmark, Melissa M. Conti, Noel Palumbo, Jessica A. George, Christopher Bishop, Corinne Y. Ostock, Nirmal Bhide |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Dyskinesia Drug-Induced Stimulation Pharmacology Motor Activity Article Clonidine Antiparkinson Agents Levodopa Rats Sprague-Dawley Cellular and Molecular Neuroscience Parkinsonian Disorders Receptors Adrenergic alpha-2 Internal medicine medicine Adrenergic alpha-2 Receptor Agonists Animals Receptor Oxidopamine business.industry Imidazoles Atipamezole Adrenergic alpha-2 Receptor Antagonists Abnormal involuntary movement Blockade Endocrinology Dyskinesia Locus coeruleus Locus Coeruleus medicine.symptom business medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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