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

Abstract

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 microg/side), WAY100635 (5 microg/side), or both (10 microg + 5 microg/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.

• Authors: Christopher Bishop, David M Krolewski, Karen L Eskow, Christopher J Barnum, Kristin B Dupre, Terrence Deak, Paul D Walker
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 87 Issue 7 Pg. 1645-58 (May 15 2009) ISSN: 1097-4547 [Electronic] United States
• PMID: 19115412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2008 Wiley-Liss, Inc.

Chemical References

• Antiparkinson Agents
• Piperazines
• Protein Precursors
• Proto-Oncogene Proteins c-fos
• Pyridines
• RNA, Messenger
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Antagonists
• Serotonin Receptor Agonists
• pre-prodynorphin
• Receptor, Serotonin, 5-HT1A
• Levodopa
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• Dynorphins
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Oxidopamine

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Antiparkinson Agents (therapeutic use)
• Corpus Striatum (drug effects)
• Dynorphins (metabolism)
• Dyskinesia, Drug-Induced (drug therapy, metabolism)
• Levodopa (adverse effects, therapeutic use)
• Male
• Motor Activity (drug effects)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, drug therapy, metabolism)
• Piperazines (pharmacology)
• Protein Precursors (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• Pyridines (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)