Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation

Discrete regions of the adult CNS, including the subventricular zone (SVZ), do retain the capacity for neurogenesis. These progenitor cells may represent a potential new source of cells for replacement therapies in neuroregenerative diseases. An understanding of the microenvironmental signals regulating neurogenesis in the adult brain would facilitate the development of such therapeutic approaches. A particularly strong expression of dopamine D-3 receptor mRNA occurs in the proliferative SVZ during prenatal and early postnatal ontogeny. Although its expression diminishes following development, a restricted D-3 receptor expression persists in this region through adulthood, coincident with continued proliferation in this region. Here, we demonstrate a two-fold induction of cell proliferation (BrdU incorporation) in the SVZ and rostral migratory stream of the adult Sprague-Dawley rat brain following intrasubventricular administration of the dopamine D-3 receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) for 2 weeks. The number of BrdU-positive cells was elevated ten-fold from very low baseline levels in the neighbouring neostriatum, another region known to express D-3 receptors. These striatal BrdU-positive cells appeared within 3 days following intracerebral infusion of 7-OH-DPAT and were distributed homogeneously throughout the striatum following systemic administration. This suggests that these cells originate from resident progenitor cells rather than the SVZ. Dopamine D-3 receptor activation may serve as a proneuronal differentiation signal as 60-70% of the new cells had neuronal markers following 7-OH-DPAT infusion. These results suggest that the dopamine D-3 receptor may be a good drug target for cell replacement strategies, particularly because of the fact that its expression is almost exclusively limited to the nervous system.