Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Abstract

Background: The gold-standard treatment for Parkinson’s disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine before uncontrolled release as a “false neurotransmitter”. The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. Objective: This study aimed to investigate the functionality of 5-HT1A receptor using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed “off” L-DOPA. Methods: Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist (which labels receptors in a high affinity state for agonists) or [18F]MPPF, a 5-HT1AR antagonist (which labels all the receptors). Results: There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased in the globus pallidus and thalamus. On the contralateral side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. Conclusion: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson’s disease and levodopa-induced dyskinesia. In particular, these observations suggest an important involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.

Motor cortico-nigral and cortico-entopeduncular information transmission and its modulation by buspirone in control and after dopaminergic denervation

“…With all, studies evaluating 5-HT 1A receptors in different regions report variable results. In hemiparkinsonian rats, we have observed a slight but significant reduction in 5-HT 1A receptor immunoreactivity in the striatum and GPe after DA loss ( Vegas-Suárez et al, 2021 ), in line with a micro-PET study ( Vidal et al, 2021 ). The use of other techniques such as autoradiography and in situ hybridization for 5-HT 1A studies failed to support those results in the striatum ( Radja et al, 1993 ; Numan et al, 1995 ).…”

Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

“…In fMRI experiments, NLX-112 also elicited functional connectivity effects in regions expressing pre-synaptic 5-HT 1A R ( Vidal et al, 2020 ). Changes in the functional state of 5-HT 1A R were also observed in HPK rats, especially when treated repeatedly with L-DOPA to elicit dyskinesia ( Vidal et al, 2021 ).…”