Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson's Disease

Molecules. 2021 Sep 24;26(19):5790. doi: 10.3390/molecules26195790.

Abstract

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.

Keywords: L-DOPA; Parkinson’s disease; cortical stimulation; dopamine; dyskinesia; serotonin; striatum.

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesia, Drug-Induced / prevention & control*
  • Gene Expression Regulation
  • Levodopa / administration & dosage*
  • Levodopa / adverse effects
  • Male
  • Oxidopamine / adverse effects*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Vilazodone Hydrochloride / administration & dosage*
  • Vilazodone Hydrochloride / pharmacology

Substances

  • Receptor, Serotonin, 5-HT1A
  • Levodopa
  • Oxidopamine
  • Vilazodone Hydrochloride