Dopamine D₃ receptor stimulation promotes the proliferation of cells derived from the post‐natal subventricular zone

Abstract

In the adult mammalian brain, neural stem cells persist in the subventricular zone (SVZ) where dopamine D 3 receptors are expressed. Here, we demonstrate that addition of 1 lM apomorphine increases cell numbers in post-natal SVZ cell cultures. This effect was prevented by a co-treatment with haloperidol, sulpiride or U-99194A, a D 3 -preferring antagonist, and mimicked by the dopamine D 3 receptor selective agonist 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). EC 50 values were 4.04 ± 1.54 nM for apomorphine and 0.63 ± 0.13 nM for 7-OH-DPAT, which fits the pharmacological profile of the D 3 receptor. D 3 receptors were detected in SVZ cells by RT-PCR and immunocytochemistry. D 3 receptors were expressed in numerous b-III tubulin immunopositive cells. The fraction of apoptotic nuclei remained unchanged following apomorphine treatment, thus ruling out any possible effect on cell survival. In contrast, proliferation was increased as both the proportion of nuclei incorporating bromo-deoxyuridine and the expression of the cell division marker cyclin D 1 were enhanced. These findings provide support for a regulatory role of dopamine over cellular dynamics in post-natal SVZ.

Dopamine D3Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

“…The preferential dopamine D 3 receptor agonist 7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) was selected for this proposal based on previous studies demonstrating its mitogenic role both in vitro (Pilon et al, 1994;Coronas et al, 2004) and in vivo (Van Kampen et al, 2004;Van Kampen and Robertson, 2005). Thus, 4 weeks after intoxication (see Fig.…”

“…Specifically, the dopamine D 3 receptor appears to play an important role in neural development and shows a persistent expression through adulthood in the proliferative SVZ (Diaz et al, 1997). Furthermore, pharmacological stimulation of D 3 receptors promotes proliferation and neuronal differentiation of adult SVZ cells, both in vitro (Coronas et al, 2004) and in vivo (Van Kampen et al, 2004), whereas activation of other dopamine receptor subtypes does not (Coronas et al, 2004;Van Kampen et al, 2004;Kippin et al, 2005). Removal of dopaminergic afferents reduces SVZ proliferation (Baker et al, 2004;Höglinger et al, 2004), an effect reversed by a dopamine D 3 receptor agonist (Höglinger et al, 2004).…”

“…Dopamine receptor activation modulates neurogenesis in both the developing (Spencer et al, 1998;Ohtani et al, 2003) and adult (Coronas et al, 2004;Van Kampen et al, 2004;Van Kampen and Robertson, 2005) brain. Specifically, the dopamine D 3 receptor appears to play an important role in neural development and shows a persistent expression through adulthood in the proliferative SVZ (Diaz et al, 1997).…”

Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain

“…In agreement with this, studies have shown that the relatively non-selective dopamine agonists, bromocriptine and apomorphine, act to stimulate adult rat SVZ-neurosphere proliferation, an effect that can be blocked by the D2L antagonist sulpiride. 14,22 Moreover, the highly selective D3 agonist 7-OH-DPAT, 22 has also been shown to have similar effects with neurosphere proliferation in vitro. However, the D1L agonist SKF 38393 has been shown to have no effect on proliferation in vitro.…”

Effects of 6-hydroxydopamine on the Adult Neurogenesis of Dopaminergic Neurons in the Mouse Midbrain

“…Because damaged neurons can be labeled with BrdU (Coronas et al, 2004;Hoglinger et al, 2004), we do not rule out the possibility that severe injury induced by the MPTP might promote the nonspecific BrdU labeling in injured neurons. Furthermore, it is known that the fusion of neurons with cells expressing BrdU can produce double labeling of BrdU and neuronal markers in a cell without actual adult neurogenesis (El-Khodor et al, 2003).…”