Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior

The presence of endogenous stem cell populations in the adult mammalian CNS suggests an innate potential for regeneration and represents a potential resource for neuroregenerative therapy aimed at the treatment of neurodegenerative disorders, such as Parkinson's disease. However, it is first necessary to examine the microenvironmental signals required to activate these innate reparative mechanisms. The small molecule neurotransmitter dopamine has been shown to regulate cell cycle in developing and adult brain, and the D-3 receptor is known to play an important role in dopaminergic development. Pharmacological activation of the dopamine D-3 receptor has been shown to trigger neurogenesis in the substantia nigra of the adult rat brain. Here, we examined the cell proliferative, neurogenic, and behavioral effects of the dopamine D-3 receptor agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) in a 6-hydroxydopamine model of Parkinson's disease. Consistent with previous findings, we observed a significant induction of cell proliferation in the substantia nigra pars compacta (SNC) with a time-dependent adoption of a neuronal dopaminergic phenotype in many of these cells. Indices of nigrostriatal integrity were also affected. Dopaminergic cell counts in the lesioned SNC recovered substantially in a time-dependent manner. Similarly, retrograde tracing revealed a restoration of striatal innervation from these cells, with evidence for projections arising from newly generated cells. Finally, we observed a substantial and persistent recovery of locomotor function in these animals. The results of these studies will further our understanding of the environmental signals regulating neurogenesis in the adult brain and could have significant implications for the design of novel treatment strategies for Parkinson's disease.