title: Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats.
abstract: Serotonin 1A receptor (5-HT(1A)R) agonists reduce both L-DOPA- and D1 receptor (D1R) agonist-mediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT(1A)R stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT(1A)R agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or sham lesions were primed with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, sc) or the D1R agonist SKF81297 (0.8 mg/kg, sc) until abnormal involuntary movements (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT(1A)R agonist ±8-OH-DPAT (1.0 mg/kg, sc), followed by L-DOPA or SKF81297, or intrastriatal ±8-OH-DPAT (7.5 or 15 mM), followed by L-DOPA. In some cases, the 5-HT(1A)R antagonist WAY100635 was employed to determine receptor-specific effects. In vivo microdialysis was used to collect striatal samples for analysis of extracellular glutamate levels during AIMs assessment. Systemic and striatal ±8-OH-DPAT attenuated L-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed ±8-OH-DPAT's effects. Interestingly, systemic ±8-OH-DPAT diminished D1R-mediated AIMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT(1A)R agonists with implications for the improved treatment of Parkinson's disease.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University (State University of New York at Binghamton), Binghamton, NY 13902-6000, USA.
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Dupre
authors.forename: Corinne Y
authors.initials: CY
authors.lastname: Ostock
authors.forename: Karen L
authors.initials: KL
authors.lastname: Eskow Jaunarajs
authors.forename: Thomas
authors.initials: T
authors.lastname: Button
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Savage
authors.forename: William
authors.initials: W
authors.lastname: Wolf
authors.forename: Christopher
authors.initials: C
authors.lastname: Bishop
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001545:Benserazide / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D018698:Glutamic Acid; D007980:Levodopa; C067113:SK&F 81297; D001545:Benserazide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine