RESUMO
Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.
Assuntos
Tamanho Corporal/fisiologia , Hormônio do Crescimento/metabolismo , Hipófise/metabolismo , Prolactina/metabolismo , Receptores de Dopamina D2/metabolismo , Análise de Variância , Animais , Benzamidas/farmacocinética , Tamanho Corporal/efeitos dos fármacos , Tamanho Corporal/genética , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Estudos de Casos e Controles , Catatonia/induzido quimicamente , Catatonia/metabolismo , Antagonistas de Dopamina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Feminino , Haloperidol/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Filamentos Intermediários/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Nestina , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Feromônios/urina , Hipófise/efeitos dos fármacos , Prolactina/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteínas/metabolismo , Radioimunoensaio , Receptores de Dopamina D2/deficiência , Receptores de Dopamina D2/genética , Predomínio Social , Territorialidade , Trítio/farmacocinéticaRESUMO
1) In the rat pituitary, angiotensin type 1B receptors (AT1B) are located in lactotrophs and corticotrophs. 2) Activation of AT1B receptors are coupled to Gq/11 (Guanine protein coupled receptor, or GPCR); they increase phospholipase beta C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP3) and diacylglycerol (DAG) formation. A biphasic increase in [Ca2+]i triggered by InsP3 and DAG ensues. 3) As many GPCRs, AT1B pituitary receptors rapidly desensitize. 4) This was observed in the generation of InsP3, the mobilization of intracellular Ca(2+), and in prolactin release. Both homologous and heterologous desensitization was evidenced. 5) Desensitization of the angiotensin II type 1 (AT1) receptor in the pituitary shares similarities and differences with endogenously expressed or transfected AT1 receptors in different cell types. 6) In the pituitary hyperplasia generated by chronic estrogen treatment there was desensitization or alteration in angiotensin II (Ang II) evoked intracellular Ca2+ increase, InsP3 generation, and prolactin release. This correlates with a downregulation of AT1 receptors. 7) In particular, in hyperplastic cells Ang II failed to evoke a transient acute peak in [Ca2+]i, which was replaced by a persistent plateau phase of [Ca2+]i increase. 8) Different calcium channels participate in Ang II induced [Ca2+]i increase in control and hyperplastic cells. While spike phase in control cells is dependent on intracellular stores sensitive to thapsigargin, in hyperplastic cells plateau increase is dependent on extracellular calcium influx. 9) Signal transduction of the AT1 pituitary receptor is greatly modified by hyperplasia, and it may be an important mechanism in the control of the hyperplastic process. 10) In the hypothalamus and brain stem there is a predominant expression of AT1A and AT2 mRNA. 11) Ang II acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. 12) Calcium channels play important roles in the Ang II induced behavioral and endocrine responses. 13) Ang II, in physiological concentrations, can activate AT1 receptors to stimulate both Ca2+ release from intracellular stores and Ca2+ influx from the extracellular space to increase [Ca2+]i in polygonal and stellate astroglia of the hypothalamus and brain stem. 14) In primary cell culture of neurons from newborn rat hypothalamus and brain stem, it has also been determined that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+) current and a stimulation of Ca2+ current. 15) In primary cell cultures derived from the subfornical organ or the organum vasculosum laminae terminalis of newborn rat pups, Ang II produced a pronounced desensitization of the [Ca2+]i response. 16) Hypothalamic and pituitary Ang II systems are involved in different functions, some of which are related. At both levels Ang II signals through [Ca2+]i in a characteristic way.