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

Academic Article

Abstract

  • 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 (12mg/kg+benserazide, 15mg/kg, sc) or the D1R agonist SKF81297 (0.8mg/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 (1.0mg/kg, sc), followed by l-DOPA or SKF81297, or intrastriatal ±8-OH-DPAT (7.5 or 15mM), 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. © 2011 Elsevier Inc.
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    Author List

  • Dupre KB; Ostock CY; Eskow Jaunarajs KL; Button T; Savage LM; Wolf W; Bishop C
  • Start Page

  • 288
  • End Page

  • 299
  • Volume

  • 229
  • Issue

  • 2