Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats

Serotonin 1A receptor (5-HT1AR) 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-HT1AR stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT1AR 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 (AlMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT1AR agonist +/- 8-0H-DPAT (1.0 mg/kg, sc), followed by L-DOPA or SKF81297, or intrastriatal +/- 8-0HDPAT (7.5 or 15 mM), followed by L-DOPA. In some cases, the 5-HT1AR 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 AlMs assessment. Systemic and striatal +/- 8-0H-DPAT attenuated L-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed +/- 8-0HDPAT's effects. Interestingly, systemic +/- 8-0H-DPAT diminished D1R-mediated AlMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT1AR agonists with implications for the improved treatment of Parkinson's disease. (C) 2011 Elsevier Inc. All rights reserved.