Pharmacologic antagonism of dopamine receptor D3 attenuates neurodegeneration and motor impairment in a mouse model of Parkinson's disease

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

“…This was discordant with our previous findings of significantly decreased [18F]-Fallypride binding in the Tg rats compared to WT rats at a similar age (5–9 months) [26]. Since we know D2/D3 receptors are expressed in many cell types other than dopaminergic neurons [19–23, 38] we believe this discrepancy could be related to loss/dysfunction of those cell types, such as astrocytes and GABAergic neurons. This could lead to D2/D3 deficits that are not fully reflective of dopaminergic loss.…”

“…While decreased [18F]-Fallypride binding in the striatum of the Tg rats compared to age-matched WT rats suggested postsynaptic dopaminergic dysfunction, we suspected that some of the decreased binding could be due to extensive astrocytic loss in this animal model [12] since astrocytes are known to express D2/D3 receptors [19–23]. Therefore, we wanted to confirm dopaminergic dysfunction by concurrently probing the postsynaptic component using [18F]-Fallypride and the presynaptic component using [18F]-FP-CMT, a dopamine transporter (DAT) ligand with good pharmacological selectivity, lack of brain penetrant metabolites and rapid kinetic profile [24].…”

Targeting dopamine receptor D3 signalling in inflammation

“…Importantly, the therapeutic effect observed in Parkinson’s disease models in our studies [7] was exerted by a highly-selective DRD3 antagonist, PG01037, displaying the Ki values 0.70, 93.3 and 375 nM for DRD3, DRD2 and DRD4 respectively. In apparent controversy with our recent findings, pramipexole, a drug described as a DRD3-agonist, has been used for the symptomatic treatment of Parkinson’s disease.…”

“…Moreover, evidence has also indicated that DRD3-signalling favours Th17-immunity under chronic inflammatory conditions [4]. According to the pivotal role of Th1 and Th17 inflammatory responses in the development of Parkinson’s disease, we have recently demonstrated the therapeutic potential of DRD3- antagonism in two different animal models, including 6-hydroxydopamine-induced and 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine-induced Parkinson’s disease [7]. In those studies, DRD3-antagonism not only reduced the neurodegenerative and neuroinflammatory process, but also attenuated significantly the motor impairment associated to the loss of dopaminergic neurons.…”

“…Our analyses performed in glial cells have suggested that DRD3-deficiency gives an anti-inflammatory behaviour to astrocytes, which results in attenuated microglial activation in a model of Parkinson’s disease [7]. Furthermore, recently we found that DRD3-deficiency or DRD3-antagonism in dendritic cells results in an exacerbated stimulation of CD8 + T-cell-mediated immunity, strengthening the immune response against tumours [8].…”