Contribution of the striatum to the effects of 5-HT1A receptor stimulation in L-DOPA-treated hemiparkinsonian rats.
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.
Bishop
Christopher
C
Behavioral Neuroscience Program, Department of Psychology, State University of New York at Binghamton, Binghamton, NY 13902, USA. cbishop@binghamton.edu
Krolewski
David M
DM
Eskow
Karen L
KL
Barnum
Christopher J
CJ
Dupre
Kristin B
KB
Deak
Terrence
T
Walker
Paul D
PD
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects*; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000978:Antiparkinson Agents; D010879:Piperazines; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012333:RNA, Messenger; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C036448:pre-prodynorphin; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004399:Dynorphins; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine