Contribution of the striatum to the effects of 5-HT1A receptor stimulation in L-DOPA-treated hemiparkinsonian rats

• Published in: Journal of neuroscience research 2009-05, Vol.87 (7), p.1645-1658
• Main Authors: Bishop, Christopher, Krolewski, David M., Eskow, Karen L., Barnum, Christopher J., Dupre, Kristin B., Deak, Terrence, Walker, Paul D.
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Antiparkinson Agents - therapeutic use; c-fos; Corpus Striatum - drug effects; Dynorphins - metabolism; Dyskinesia, Drug-Induced - drug therapy; Dyskinesia, Drug-Induced - metabolism; L-DOPA-induced dyskinesia; Levodopa - adverse effects; Levodopa - therapeutic use; Male; Motor Activity - drug effects; Oxidopamine; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - metabolism; Piperazines - pharmacology; preprodynorphin; Protein Precursors - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; RNA, Messenger - metabolism; serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.21978

Clinical and experimental studies implicate the use of serotonin (5‐HT)1A receptor agonists for the reduction of L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia (LID). Although raphe nuclei likely play a role in these antidyskinetic effects, an unexplored population of striatal 5‐HT1A receptors (5‐HT1AR) may also contribute. To better characterize this mechanism, L‐DOPA‐primed hemiparkinsonian rats received the 5‐HT1AR agonist ±8‐OH‐DPAT (0, 0.1, 1.0 mg/kg, i.p.) with or without cotreatment with the 5‐HT1AR antagonist WAY100635 (0.5 mg/kg, i.p.) 5 min after L‐DOPA, after which abnormal involuntary movements (AIMs), rotations, and forelimb akinesia were quantified. To establish the effects of 5‐HT1AR stimulation on L‐DOPA‐induced c‐fos and preprodynorphin (PPD) mRNA within the dopamine‐depleted striatum, immunohistochemistry and real‐time reverse transcription polymerase chain reaction, respectively, were used. Finally, to determine the contribution of striatal 5‐HT1AR to these effects, L‐DOPA‐primed hemiparkinsonian rats received bilateral intrastriatal microinfusions of ±8‐OH‐DPAT (0, 5, or 10 μg/side), WAY100635 (5 μg/side), or both (10 μg + 5 μg/side) 5 min after L‐DOPA, after which AIMs and rotations were examined. Systemic ±8‐OH‐DPAT dose‐ and receptor‐dependently attenuated L‐DOPA‐mediated AIMs and improved forelimb akinesia. Striatal c‐fos immunoreactivity and PPD mRNA ipsilateral to the lesion were strongly induced by L‐DOPA, while ±8‐OH‐DPAT suppressed these effects. Finally, intrastriatal infusions of ±8‐OH‐DPAT reduced AIMs while coinfusion of WAY100635 reversed its antidyskinetic effect. Collectively, these results support the hypothesis that the cellular and behavioral properties of 5‐HT1AR agonists are conveyed in part via a population of functional 5‐HT1AR within the striatum. © 2008 Wiley‐Liss, Inc.