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Disruption of the D2 Dopamine Receptor Alters GH and IGF-I Secretion and Causes Dwarfism in Male Mice

Instituto de Biología y Medicina Experimental (G.D.-T., C.L., D.B.-V.), Instituto de Ingeniería Genética (D.G., M.R.), Consejo Nacional de Investigaciones Científicas y Técnicas; and Agencia Nacional de Promoción Científica y Tecnológica, SECYT (C.F.), 1428 Buenos Aires, Argentina; The Vollum Institute, Oregon Health and Science University (M.A.K., M.J.L.), Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. D. Becú-Villalobos, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas V, Obligado 2490, 1428 Buenos Aires, Argentina. E-mail: . dbecu{at}dna.uba.ar

We determined the consequences of the loss of D2 receptors (D2R) on the GH-IGF-I axis using mice deficient in functional dopamine D2 receptors by targeted mutagenesis (D2R^-/-). Body weights were similar at birth, but somatic growth was less in male D2R^-/- mice from 1–8 months of age and in D2R^-/- females during the first 2 months. The rate of skeletal maturation, as indexed by femur length, and the weight of the liver and white adipose tissue were decreased in knockout male mice even though food intake was not altered. The serum GH concentration was significantly decreased during the first 2 months in knockout female and male mice, and IGF-I and IGF-binding protein-3 levels were lower in knockout mice. PRL was significantly higher in knockout mice, and females attained higher levels than males. Pituitaries from adult knockout mice had impaired basal GH release and a lower response to GHRH in vitro. We propose that the D2R participates in GHRH/GH release in the first month of life. In accordance, the D2R antagonist sulpiride lowered GH levels in 1-month-old wild-type mice. Our results indicate that lack of D2R alters the GHRH-GH-IGF-I axis, and impairs body growth and the somatotrope population.

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