NeuralCipher Research overview
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Abstract Parkinson’s Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). Along with motor deficits, patients often present with debilitating non-motor symptoms like PD-associated psychosis (PDAP) which includes sensorimotor gating deficits and hallucinations that worsen over time. The pathophysiology of PDAP has been suggested to involve serotonin (5-HT), and in particular, 5-HT2 receptors (5-HT 2 R) which are upregulated in the basal ganglia and cortices of PD patients and in experimental models. To investigate this, the present study utilized a novel multimodal visual-auditory prepulse inhibition (PPI) assay in hemiparkinsonian rats. In Experiment 1, unilateral 6-hydroxydopamine (6-OHDA)-lesioned and sham rats were assessed for sensorimotor gating using multimodal PPI. Experiment 2 used PPI and the 5-HT 2A/2C R agonist, ± 2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) to investigate the role of 5-HT 2 R in PPI, Head Twitch Response (HTR), a measure of hallucinogenic-like activity, and rearing to gauge anxiogenic-like effects. Findings in Experiment 1 revealed that 6-OHDA-lesions significantly reduced PPI vs. non-lesioned animals at the longest prepulse interval. In Experiment 2, DOI disrupted PPI in DA-lesioned rats at lower doses and shorter intervals than sham-lesioned rats. DA-lesioned animals also displayed significantly greater DOI-induced HTR compared to sham animals at the highest dose and less rearing at a low dose of DOI. Post-mortem analyses revealed reduced DA and 5-HT in the striatum, basolateral amygdala, medial prefrontal cortex. Overall, these findings with multimodal PPI implicate maladaptive sensorimotor gating in the parkinsonian brain, an enhanced role for 5-HT 2 R in these effects and important therapeutic targets for PD patients experiencing PDAP.
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