Growth hormone receptor in dopaminergic neurones regulates stress‐induced prolactin release in male mice

Abstract

Arcuate nucleus (ARH) dopaminergic neurones regulate several biological functions, including prolactin secretion and metabolism. These cells are responsive to growth hormone (GH), although it is still unknown whether GH action on ARH dopaminergic neurones is required to regulate different physiological aspects. Mice carrying specific deletion of GH receptor (GHR) in tyrosine hydroxylase (TH)‐ or dopamine transporter (DAT)‐expressing cells were produced. We investigated possible changes in energy balance, glucose homeostasis, fertility, pup survival and restraint stress‐induced prolactin release. GHR deletion in DAT‐ or TH‐expressing cells did not cause changes in food intake, energy expenditure, ambulatory activity, nutrient oxidation, glucose tolerance, insulin sensitivity and counter‐regulatory response to hypoglycaemia in male and female mice. In addition, GHR deletion in dopaminergic cells caused no gross effects on reproduction and pup survival. However, restraint stress‐induced prolactin release was significantly impaired in DAT‐ and TH‐specific GHR knockout male mice, as well as in pegvisomant‐treated wild‐type males, whereas an intact response was observed in females. Patch clamp recordings were performed in ARH DAT neurones and, in contrast to prolactin, GH did not cause acute changes in the electrical activity of DAT neurones. Furthermore, TH phosphorylation at Ser40 in ARH neurones and median eminence axonal terminals was not altered in DAT‐specific GHR knockout male mice during restraint stress. In conclusion, GH action in dopaminergic neurones is required for stress‐induced prolactin release in male mice, suggesting the existence of sex differences in the capacity of GHR signalling to affect prolactin secretion. The mechanism behind this regulation still needs to be identified.

Effects of Growth Hormone Receptor Ablation in Corticotropin-Releasing Hormone Cells

“…Therefore, GH action in CRH neurons does not modulate the acute responses to stress. In contrast to our findings, GHR signaling in dopamine neurons regulates prolactin release during restraint stress [ 32 ]. GHR ablation in VMH neurons acutely impairs the counterregulatory response induced by 2DG or insulin [ 5 ], which is another form of metabolic stress.…”

“…Plasma samples were obtained after centrifuging blood collected from the tail vein using heparinized capillaries (75 mm length and 1.5 mm diameter). To determine restraint-stress-induced corticosterone secretion, mice at 09:00 a.m. were physically restrained for 120 min in 50 mL polypropylene centrifuge tubes, containing holes of 0.4 cm diameter to breathe, as previously described [ 32 ]. A small cut in the tail tip was performed to allow blood collection using heparinized capillaries.…”

“…These areas include the arcuate nucleus (ARH), ventromedial nucleus (VMH), paraventricular nucleus of the hypothalamus (PVH), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CEA) and locus coeruleus [ 25 , 26 ]. In the ARH, GH acts in several distinct neuronal populations, such as neurons that express agouti-related protein (AgRP) [ 11 , 23 , 27 , 28 , 29 , 30 ], proopiomelanocortin (POMC) [ 31 ], tyrosine hydroxylase [ 32 , 33 ] or choline acetyltransferase [ 34 ]. The role of GHR signaling in these neuronal populations is starting to be unraveled.…”

“…Another study has shown that GHR signaling in hypothalamic neurons regulates the adaptation capacity to aerobic exercise in a cell-specific manner [ 6 ]. Furthermore, GHR expression in dopaminergic neurons modulates stress-induced prolactin release [ 32 ]. Thus, central GH action promotes metabolic and neuroendocrine adaptations in different situations of metabolic stress.…”

Metabolic Effects of Clozapine Administration Based on Sex Differences and the Relationships Between Dosage and Prolactin Levels: An Observational Study

“…Auriemma et al 32 reported that fasting insulin and insulin selective index in hyperprolactinemic male patients have been found to significantly improve after treatment with dopamine agonist. Basic experiments showed that in female mice, cholesteryl ester transfer protein, a lipid shuttling protein, is essential for HDL-C metabolism, and cholesteryl ester transfer protein is estrogen-dependent 33 ; in male mice, the presence of growth hormone is essential for dopaminergic neurons to secrete prolactin, and growth hormone influences blood glucose levels 34 . Consequently, we found the negative correlation between serum HDL-C levels and prolactin levels in female subjects, and the positive correlation between FBS levels and prolactin levels in male subjects, which may be due to the existence of sex differences in prolactin secretion and metabolic processes.…”