The alteration of dopamine receptors in L-DOPA (L-3,4-dihydroxyphenylalanine) induced dyskinesias.

Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) can ease symptoms of Parkinson’s disease (PD), butextended use of L-DOPA causes abnormal involuntary movements (AIMs) called L-DOPA induced dyskinesias (LIDs). The present study aims to investigate alterations in HPA axis stimulation, neuroinflammation, DA signalling, and cholinergic signalling using molecular markers in a rat model of LIDs. A unilateral 6-hydroxydopamine (6-OHDA) lesion in the medial forebrain bundle of male Sprague-Dawley rats was used to model Parkinsonism. The PD rat model was treated with L-DOPA to further model LIDs. L-DOPA treated groups included rodents treated for 14 days and rats that developed AIMs during 28 days of treatment. LIDs severity was rated using the AIMs score. Motor skills were assessed using the elevated beam walking test. Cognitive functions were assessed using the Morris water maze test and the novel object recognition test. The concentrations of tumour necrosis factor-alpha (TNF-α), corticosterone, acetylcholinesterase (AChE), and dopamine (DA), and the expressions of D1 receptor (D1R) and D2 receptor (D2R) were quantified. L-DOPA treatment for 14 days improved the 6-OHDA-induced hypokinesia, incoordination, spatial learning, and spatial memory but did not improve recognition memory impairment. Prolonged (28 days) L-DOPA treatment led to AIMs development and failed to improve 6-OHDA-induced spatial memory impairment. L-DOPA treatment significantly increased striatal TNF-α and striatal DA concentration, cerebellar TNF-α and DA concentration, prefrontal cortex (PFC) DA and AChE concentration, but significantly reduced striatal AChE concentration, the concentration of TNF-α and D1R expression in the PFC, plasma corticosterone, and hippocampal AChE concentration. When treatment was prolonged for 28 days, striatal D2R expression significantly increased, while cerebellar TNF-α and DA concentration significantly decreased. Increased striatal D2R signalling increases motor output since the direct basal ganglia (BG) pathway is activated in LIDs. The present study showed significantly increased cerebellar DA concentration in response to BG hypoactivity; however, as striatal D2R increased cerebellar DA decreased. The connectivity between the BG and cerebellum in PD increases off L-DOPA and lowers On L-DOPA. The cognitive decline in the 6-OHDA lesioned rodents and those treated with L-DOPA results from increased AChE concentration. High AChE concentration leads to increased ACh catabolism which impairs cognitive function.