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: Kristin B Dupre, Corinne Y Ostock, Karen L Eskow Jaunarajs, Thomas Button, Lisa M Savage, William Wolf, Christopher Bishop
• Journal: Experimental neurology (Exp Neurol) Vol. 229 Issue 2 Pg. 288-99 (Jun 2011) ISSN: 1090-2430 [Electronic] United States
• PMID: 21352823 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antiparkinson Agents
• Benzazepines
• Dopamine Agonists
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• Glutamic Acid
• Levodopa
• SK&F 81297
• Benserazide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Oxidopamine

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Antiparkinson Agents (pharmacology)
• Benserazide (pharmacology)
• Benzazepines (pharmacology)
• Chromatography, High Pressure Liquid
• Corpus Striatum (drug effects, metabolism)
• Dopamine Agonists (pharmacology)
• Dyskinesia, Drug-Induced (metabolism)
• Glutamic Acid (metabolism)
• Levodopa (pharmacology)
• Male
• Microdialysis
• Neurons (drug effects, metabolism)
• Oxidopamine
• Parkinson Disease, Secondary (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Serotonin Receptor Agonists (pharmacology)