Pharmacological or genetic blockade of the dopamine D3 receptor increases cell proliferation in the hippocampus of adult mice

Abstract

Dopamine plays an important role in cellular processes controlling the functional and structural plasticity of neurons, as well as their generation and proliferation, both in the developing and the adult brain. The precise roles of individual dopamine receptors subtypes in adult neurogenesis remain poorly defined, although D3 receptors are known to be involved in neurogenesis in the subventricular zone. By contrast, very few studies have addressed the influence of dopamine and D3 receptors upon neurogenesis in the subgranular zone of the hippocampus, an issue addressed herein employing constitutive D3 receptor knockout mice, or chronic exposure to the preferential D3 receptor antagonist, S33138. D3 receptor knockout mice revealed increased baseline levels of cell proliferation and ongoing neurogenesis, as measured both using Ki-67 and doublecortin, whereas there was no difference in cell survival as measured by BrdU (5-bromo-2'-deoxyuridine). Chronic administration of S33138 was shown to be functionally active in enhancing levels of the plasticity-related molecule, delta-FosB, in the D3 receptor-rich nucleus accumbens. In accordance with the stimulated neurogenesis seen in D3 receptor knockout mice, S33138 increased proliferation in wild-type mice. These observations suggest that D3 receptors exert a tonic, constitutive inhibitory influence upon adult hippocampal neurogenesis.