The Role of Dopamine Replacement on the Behavioural Phenotype of Parkinson’s Disease

Abstract

Abstract. Objectives:The pharmacotherapy of Parkinson's disease (PD) is often challenging as clinicians have to find a favourable balance between the efficacy on motor symptoms and side effect profiles of different dopaminergic medications. We aimed to assess the available evidence on the role of dopamine agonist monotherapy as an alternative to Levodopa in the treatment of motor symptoms of PD, along with the role of dopamine antagonists in the treatment of PD-related psychosis. Methods: We performed a systematic literature review using the databases MEDLINE, EMBASE, PsycINFO and the Cochrane Library Central register of controlled trials. Two searches were performed, 'Search 1' extracting trials on dopamine agonists, and 'Search 2' on atypical antipsychotics. Eligible studies were Double-blind Randomised Controlled Trials (RCTs) using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Brief Psychiatric Rating Scale (BPRS) as outcome measures for Search 1 and 2, respectively. Results: 16 relevant RCTs were extracted from the search results. Overall, dopamine agonists were shown to significantly improve UPDRS scores, with a mean percentage improvement of 14.4% compared to −1.9% in the control arm (P value < 0.05). However, their side effect profile illustrated they were associated with twice the incidence of psychotic symptoms in comparison to the controls. The results on the efficacy of atypical antipsychotics for the treatment of PD-related psychosis were not significant. Conclusions: This evidence-based review confirmed that dopamine agonists can be an effective and safe treatment as monotherapy in PD, however psychotic symptoms remain a significant side effect. Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy.

Efficient and biologically relevant consensus strategy for Parkinson’s disease gene prioritization

“…Since the final 50 genes comes from the intersection of the prioritizations made by Limma , WGCNA modules, and specially ML, a reduced statistical significance of their biological processes should be expected too, similarly to ML. Most of the top enriched GO terms in the biological process enrichment analysis are associated with PD: dopamine (DA) metabolism [ 59 – 63 , 67 – 80 ]; prepulse inhibition (PPI) [ 81 – 86 ]; metal ion transport and pigmentation [ 87 – 96 ]. None of the biological processes is statistically significant by using an FDR adjusted p-value < 0.05 as significance cutoff.…”

The neurobiological basis of cognitive impairment in Parkinson's disease

“…There is greater degeneration of medial A9 dopamine neurons in PDD, and potentially related to this cell loss are findings in the caudate nucleus and ventral striatum of a loss of presynaptic dopamine in PDD as well as a correlation between the density of postsynaptic D1 dopamine receptors and cognitive impairment . These medial mesolimbic A9 dopamine neurons play an important role in behavioral selection and impulsivity, and enhanced function in mesolimbic/ventral striatal dopaminergic circuits subsequent to dopamine agonist use may contribute to impulse control disorders in PD …”

“…48,49 The largest group of dopamine neurons (A9 group) are found in the SN, an integral part of the basal ganglia that provides a feedback loop to the striatum important for control of actions and thoughts. The ventrolateral A9 neurons that project to the putamen degenerate early before LB formation in PD, 50 with increasing degeneration of other A9 nigrostriatal neurons relating to increasing motor deficits as the disease progresses, 51,52 deficits that are initially ameliorated by dopamine replacement therapies 53 and enhanced by the use of dopamine blocking drugs. 54 A number of histopathological 52,55 and imaging 56-58 studies show that the severity of A9 dopamine loss is independent of dementia in PD.…”

“…64 These medial mesolimbic A9 dopamine neurons play an important role in behavioral selection and impulsivity, 59 and enhanced function in mesolimbic/ventral striatal dopaminergic circuits subsequent to dopamine agonist use may contribute to impulse control disorders in PD. 53,65 The ventral tegmental area A10 dopamine neurons are considered integral in both reward behaviors (mesolimbic) and cognitive functions (mesocortical), 49 but are less studied in patients with PD. In humans, the A10 dopamine neurons are spread over a large rostrocaudal region of the midbrain and are difficult to identify with certainty in single sections.…”

Gastrointestinal dysfunction in idiopathic Parkinsonism: A narrative review

“…Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy. [58] Second, dopamine stimulates rectosigmoid motility in contrast to its known inhibitory effect on upper GI motility. This appears to be mediated by specific dopamine receptors and may therefore worsen the underlying gastroparesis,[18] thereby contributing to nausea, vomiting, and other GI symptoms.…”