| First Author | Wang Y | Year | 2020 |
| Journal | Exp Neurol | Volume | 333 |
| Pages | 113427 | PubMed ID | 32735872 |
| Mgi Jnum | J:301242 | Mgi Id | MGI:6503370 |
| Doi | 10.1016/j.expneurol.2020.113427 | Citation | Wang Y, et al. (2020) The antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons. Exp Neurol 333:113427 |
| abstractText | The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement in Pitx3Null mice; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement in Pitx3Null mice; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD. |
