The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

Abstract

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

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

“…Our main results can be summarized as follows. First, our findings confirm and extend previous results by us [ 54 ] and others [ 53 ], demonstrating a powerful inhibitory effect of vilazodone on the various subtypes of L-DOPA-induced dyskinesia (AIMs) observed in this model. Second, importantly, in contrast to other serotonergic modulatory agents, vilazodone co-administration did not compromise the therapeutic efficacy of L-DOPA, as shown by our outcomes in the forelimb stepping test.…”

“…Fourth, in line with the behavioral effects of vilazodone, our in vivo electrophysiological studies revealed that vilazodone prevented the abnormal L-DOPA-induced facilitation of corticostriatal transmission (reflected by a decrease in onset latency of cortically evoked spikes in MSNs), and that these vilazodone effects were also attenuated by blocking 5-HTr 1A . These results complement our previous findings showing that vilazodone suppresses abnormal L-DOPA-induced gene regulation in MSNs in this model [ 54 ]. Collectively, these findings indicate that vilazodone co-treatment is capable of “normalizing” aberrant MSN activities and corticostriatal transmission that contribute to L-DOPA-induced dyskinesia, and that 5-HT 1A serotonin receptors mediate these vilazodone effects.…”

“…In contrast, studies investigating vilazodone did not observe symptoms of 5-HT syndrome, even at higher doses [ 49 , 53 , 67 ]. Moreover, importantly, our findings demonstrate that vilazodone co-administration, at the present intermediate dose (10 mg/kg), which largely suppressed L-DOPA-induced abnormal gene regulation in striatal MSNs [ 54 ], did not interfere with the prokinetic efficacy of L-DOPA, as assessed in the forelimb stepping test (present results; [ 54 ]), although higher doses may lose some of this advantage [ 53 ].…”

“…Vilazodone differs from previous agents in that it combines 5-HTr 1A partial agonist activity with its SSRI properties [ 50 , 51 , 52 ]. Early findings showed that vilazodone attenuated development and expression of L-DOPA-induced dyskinesia at doses that did not interfere with L-DOPA’s prokinetic efficacy [ 53 , 54 ]. Moreover, vilazodone also suppressed L-DOPA-induced aberrant gene regulation in striatal MSNs, a molecular correlate of L-DOPA-induced dyskinesia [ 54 ].…”

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…Several activated products were obtained in moderate to good yields (Scheme 40B). The authors extrapolated this methodology, using it to synthesize a derivative of vilazodone (135, Scheme 40C), a known antidepressant drug commercialized under the name viibryd which also bears potential activity against Parkinson's disease [203]. In previous studies it has been observed that 2-phenoxypyridines belong to a class of compounds that presents potent herbicidal properties (136, 137, Scheme 41A) [204].…”