Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease.

Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.

The effects of L-DOPA on gait abnormalities in a unilateral 6-OHDA rat model of Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine's anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT1A antagonist WAY-100635 or 5-HT1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine's effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT1A and 5-HT1B receptors each partially reversed vortioxetine's effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects.

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats.

Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1A agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients.

The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats.

Parkinson's disease is a neurodegenerative disease often characterized by motor deficits and most commonly treated with dopamine replacement therapy. Despite its benefits, chronic use of L-DOPA results in abnormal involuntary movements known as L-DOPA-induced dyskinesia. Growing evidence shows that with burgeoning dopamine cell loss, neuroplasticity in the serotonin system leads to the development of L-DOPA-induced dyskinesia through the unregulated uptake, conversion, and release of L-DOPA-derived dopamine into the striatum. Previous studies have shown that coincident 5-HT1A agonism and serotonin transporter inhibition may have anti-dyskinetic potential. Despite this, few studies have explicitly focused on targeting both 5-HT1A and the serotonin transporter. The present study compares the 5-HT compounds Vilazodone, YL-0919, and Vortioxetine which purportedly work as simultaneous 5-HT1A receptor agonists and SERT blockers. To do so, adult female Sprague Dawley rats were rendered hemiparkinsonian and treated daily for two weeks with L-DOPA to produce stable dyskinesia. The abnormal involuntary movements and forehand adjusting step tests were utilized as measurements for L-DOPA-induced dyskinesia and motor performance in a within-subjects design. Lesion efficacy was determined by analysis of striatal monoamines via high-performance liquid chromatography. Compounds selective for 5-HT1A/SERT target sites including Vilazodone and Vortioxetine significantly reduced L-DOPA-induced dyskinesia without compromising L-DOPA pro-motor efficacy. In contrast, YL-0919 failed to reduce L-DOPA-induced dyskinesia, with no effects on L-DOPA-related improvements. Collectively, this work supports pharmacological targeting of 5-HT1A/SERT to reduce L-DOPA-induced dyskinesia. Additionally, this further provides evidence for Vilazodone and Vortioxetine, FDA-approved compounds, as potential adjunct therapeutics for L-DOPA-induced dyskinesia management in Parkinson's patients.