The function of dopamine (DA) in the nervous system is paralleled by its neuroendocrine control of pituitary gland functions. Here, we document the neuroendocrine function of dopamine by studying the pituitary gland of mice lacking DA D2 receptors (D2R). These mice present a striking, progressive increase in lactotroph number, which ultimately leads to tumors in aged animals. Females develop tumors much earlier than males. An estrogen-mediated lactotroph proliferation cannot account for this sexual dimorphism, since D2R-null females are hypoestrogenic and, thus, have estrogen levels similar to males. In contrast, prolactin levels are six times higher in females than in males. We show that active prolactin receptors are present in the pituitary and their expression increases in concomitance with tumor expansion. These results point to prolactin as an autocrine proliferative factor in the pituitary gland. Additionally, they demonstrate an antiproliferatire function for DA regulated through D2 receptor activation.
Bibliographical noteFunding Information:
We acknowledge Drs. A. Giangrande, P. Sassone-Corsi, N. Foulkes, P. Sawchenko, and members of the laboratory for discussions. We thank Drs. H. Kercret (INSERM, Rennes, France) for the PRL RIA and P. Mellon (UCSD, San Diego, California) for cDNA probes . We are grateful to G. Thiriet for technical assistance, W. Magnant and S. Falcone for animal care, B. Boulay and J. M. Lafontaine for artwork, and J. L. Vonesch for image analyses. A. S., Y. B., and J.-H. B. were supported by fellowships from the European Economic Community, Fondation pour la Recherche Medicale, and Fyssen Foundation, respectively. This work was supported by funds from CNRS, INSERM, CHU, and Association pour la Recherche sur le Cancer to E. B.
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