Central dopamine D2 receptors integrate a neuroendocrine-exocrine cascade that controls body growth, social dominance and territorial behaviors

NOAIN D; PEREZ MILLAN, MI; E. BELLO-GAY; LUQUE G; CASAS CORDERO R; GELMAN DIEGO; M. PEPER; GARCÍA TORNADÚ ISABEL; LOW,M.J.; BECU-VILLALOBOS DAMASIA; RUBINSTEIN,M.

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2012

0270-6474

ACEPTADO EN 2012. PUBLICADO EN 2013. J Neurosci. 2013 Mar 27;33(13):5834-42. doi: 10.1523/JNEUROSCI.5673-12.2013. The dopamine D2 receptor (D2R) is expressed in most brain dopamine (DA) target areas and controls locomotor activity and reward-seeking behaviors. The D2R is also expressed in pituitary lactotropes where it mediates the tonic inhibitory control that DA exerts on prolactin synthesis and release. The physiological significance of this inhibitory control has been appreciated in mice lacking D2Rs (Drd2-/-) that display hyperprolactinemia (Kelly et al., 1997) and develop pituitary hyperplasia (Kelly et al., 1997; Asa et al., 1999). Analysis of Drd2-/- mice also revealed the unexpected importance of D2Rs in the regulation of the growth hormone (GH) axis and control of body size (Díaz-Torga et al., 2002). Drd2-/- mice display a shortfall of pituitary somatotropes, reduced GH and IGF-1 serum levels and, as a result, are dwarfs (Díaz-Torga et al., 2002). The abnormally large lactotrope/somatotrope ratio observed in Drd2-/- mice is highly reminiscent of a similar phenomenon observed in lactating females, where suckling-induced inhibition of tuberoinfundibular DA neurons reduces lactotrope D2R stimulation and promotes differentiation of somatolactotrope precursors into functional lactotropes  (Porter et al., 1990; Porter et al., 1991). Thus, it is conceivable that pituitary D2Rs play a critical role in establishing the terminal differentiation ratio of these two cell types from their common somatolactotrope precursor (Cohen, 2000; Scully and Rosenfeld, 2002) and, therefore, in shaping the GH axis. An alternative hypothesis that may account for the somatotrope shortfall and dwarfism of Drd2-/- mice is that lack of central D2Rs impairs growth hormone-releasing hormone (GHRH) function. GHRH is a primary GH secretagogue released from arcuate hypothalamic neurons that acts as a major trophic factor for somatotropes during pituitary development. In fact, the phenotype observed in Drd2-/- mice is similar to that present in lit/lit mice that lack functional GHRH receptors (Lin et al., 1993; Godfrey et al., 1993), and in mutant mice lacking Ghrh (Alba and Salvatori, 2004) that have a small number of somatotropes and display extreme dwarfism. To determine whether GH insufficiency in Drd2-/- mice was due to the lack of D2Rs in pituitary lactotropes or in the brain we conducted a functional dissection strategy based on cell-specific Drd2 inactivation in conditional Drd2 mutant mice (Bello et al., 2011). To this end we developed a novel strain of transgenic mice expressing Cre recombinase from a mouse prolactin gene promoter, Tg(Prl-cre)1Mrub, that in parallel with transgenic mice expressing Cre from a rat nestin promoter, Tg(Nes-cre)1Kln/J (Zimmerman et al., 1994; Tronche et al., 1999), were used to eliminate D2Rs selectively from pituitary lactotropes or from cells of neural origin. In this study we demonstrate that mice lacking D2Rs in pituitary lactotropes (lacDrd2KO) displayed normal growth curves in contrast with those lacking D2Rs in the brain (neuroDrd2KO) that are dwarfs. As a downstream consequence of GH deficiency, neuroDrd2KO male mice produced low levels of male urinary pheromones and failed to promote territorial and aggressive behaviors towards other conspecific males. Thus, our study reveals that central D2Rs controls a neuroendocrine/exocrine multimolecular cascade that is critical for social dominance between adult males and, consequently, adaptive for reproductive success.