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

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.

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

“…Consistent with previous research (Altwal et al, 2021; Guimarães et al, 2022), our data revealed that MSNs in dyskinetic animals exhibited reduced spike onset latency following cortical stimulation compared with sham‐operated animals, suggesting increased MSN excitability. The onset latency, which reflects the time required to respond to stimulus onset, is a functional property of MSNs.…”

Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum

“…Specifically, L-DOPA-induced dyskinesias were assessed (see [ 14 ] for detailed descriptions of these behaviors and their quantification). All rats with such dopamine lesions developed mid- to high levels of L-DOPA-induced dyskinesias during the repeated L-DOPA treatment (see [ 14 ]), similar to our previously reported findings after such treatments [ 16 ]. In animals co-treated with TP-10 (6/LD + TP), dyskinesias were partly inhibited (in preparation).…”

Exploring adverse events of Vilazodone: evidence from the FAERS database

“…Sleep Disorders: Including Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia, these could stem from Vilazodone's modulation of neurotransmitters and the sleep cycle. As a selective serotonin reuptake inhibitor and 5-HT1A receptor agonist, Vilazodone impacts the levels of serotonin and other neurotransmitters like dopamine and norepinephrine [18,19]. This influence might lead to sleep paralysis (due to an imbalance in REM sleep regulation), Hypnagogic hallucination, and Tachyphrenia (due to alterations in cognitive processes and perception).…”