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 (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT1AR 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-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 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-HT1AR agonists with implications for the improved treatment of Parkinson's disease.

Research Highlights
► l-DOPA treatment augmented glutamate in the DA-depleted striatum.
► D1R agonist administration did not modify striatal glutamate levels.
► 5-HT1AR agonism diminished l-DOPA-induced striatal glutamate efflux and dyskinesia.
► 5-HT1AR agonism reduced D1R-mediated dyskinesia without affecting striatal glutamate.