Effects of chemogenetic inhibition of serotonergic raphe-striatal neurons on L-DOPA-induced behaviors and neurochemistry in a rat model of Parkinson’s disease

Parkinson’s disease (PD) arises from the loss of nigrostriatal dopamine (DA) neurons in the substantia nigra pars compacta (SNc) precipitating motor impairments such as tremor, rigidity, and akinesia. DA replacement therapy via levodopa (L-DOPA), though effective, often results in the development of levodopa-induced-dyskinesia (LID), characterized by excessive hyperkinetic choreic and dystonic movements. While a myriad of mechanisms are implicated in LID, maladaptive neuroplasticity within raphe-striatal serotonin (5-HT) neurons appear to influence LID induction and severity. Although prior work has established a link between the 5-HT system and LID, tools utilized have been limited and the mechanism(s) remains elusive. Thus, the current set of experiments implemented a chemogenetic strategy by employing inhibitory DREADD (designer receptors exclusively activated by designer drugs) hM4Di expression specifically in 5-HT neurons of the DRN of hemi-parkinsonian TPH2-CRE transgenic rats, followed by chronic L-DOPA treatment. To assess the influence of DRN 5-HT inhibition on established LID, DREADD ligand C21 (0, 0.5, 3, 6 mg/kg, i.p.) was systemically administered in a within-subjects design in Experiment 1. In Experiment 2, we administered C21 (0, 0.1, 1.0 mM) directly into the DA-lesioned striatum via reverse in vivo microdialysis to determine if local DREADD-mediated 5-HT terminal inhibition per se, altered established LID. Results revealed C21 suppressed LID systemically (Experiment 1) and intrastriatally (Experiment 2) as well as reduced L-DOPA-induced striatal DA release. Post-mortem analyses revealed that nigrostriatal denervation alongside L-DOPA resulted in striatal reorganization of 5-HT innervation, highlighting a key component of raphe-striatal dysfunction in the expression of LID. In patients with Parkinson’s disease, chronic treatment with levodopa often results in disordered hyperkinetic movements, coined levodopa-induced dyskinesia (LID). While LID is prominent and debilitating, the underlying mechanisms by which LID manifests remain not fully understood. Although a myriad of mechanisms underlying LID likely contribute, the influence of raphe-striatal serotonin plasticity and compensation within the basal ganglia are especially promising. Here, we demonstrate that dyskinetic, TPH2-Cre rats bearing the inhibitory designer receptor exclusively activated by designer drugs (DREADD) hM4Di on raphe-striatal serotonin cells display reduced dyskinetic behaviors following systemic and intrastriatal infusion of the DREADD agonist compound 21. Moreover, DREADD activation attenuated extracellular dopamine following levodopa treatment, coinciding with behavioral improvements. Along with evidence of structural raphe-striatal hyperinnervation, these findings highlight the key role of (maladaptive) serotonergic raphe-striatal plasticity in LID and further illuminate this key target for its treatment.