ABSTRACT
The neurosteroid allopregnanolone, a reduced metabolite of progesterone, induces anxiolytic effects by enhancing GABA(A) receptor function. Neuropeptide Y (NPY) and GABA are thought to interact functionally in the amygdala, and this interaction may be important in the regulation of anxiety. By using Y(1)R/LacZ transgenic mice, which harbour a fusion construct comprising the promoter of the mouse gene for the Y(1) receptor for NPY linked to the lacZ gene, we previously showed that long-term treatment with benzodiazepine receptor ligands modulates Y(1) receptor gene expression in the medial amygdala. We have now investigated the effects of prolonged treatment with progesterone or allopregnanolone on Y(1)R/LacZ transgene expression, as determined by quantitative histochemical analysis of beta-galactosidase activity. Progesterone increased both the cerebrocortical concentration of allopregnanolone and beta-galactosidase expression in the medial amygdala. Finasteride, a 5alpha-reductase inhibitor, prevented both of these effects. Long-term administration of allopregnanolone also increased both the cortical concentration of this neurosteroid and transgene expression in the medial amygdala. Treatment with neither progesterone nor allopregnanolone affected beta-galactosidase activity in the medial habenula. These data suggest that allopregnanolone regulates Y(1) receptor gene expression through modulation of GABA(A) receptor function, and they provide further support for a functional interaction between GABA and neuropeptide Y in the amygdala.
Subject(s)
Amygdala/physiology , Desoxycorticosterone/analogs & derivatives , Gene Expression/drug effects , Pregnanolone/pharmacology , Progesterone/pharmacology , Receptors, Neuropeptide Y/genetics , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Desoxycorticosterone/metabolism , Female , Mice , Mice, Transgenic , Osmolar Concentration , Pregnanolone/metabolism , Progesterone/metabolism , Time FactorsABSTRACT
NPY is a potent orexigenic signal and represents a key component of targets through which leptin exerts a regulatory restraint on body adiposity. Part of the orexigenic effects of NPY are mediated by hypothalamic NPY-Y(1) receptors. Here we studied the effect of fasting, leptin, and glucose administration on Y(1) receptor gene expression using a transgenic mouse model carrying a mouse Y(1) receptor/LacZ fusion gene. Transgene expression was determined by quantitative analysis of beta-galactosidase histochemical staining in the paraventricular, arcuate, ventromedial, and dorsomedial hypothalamic nuclei and in the medial amygdala, as a control region. Food deprivation for 72 h decreased transgene expression in the paraventricular nucleus but not in the arcuate nucleus. Leptin treatment, that was per se ineffective, counteracted the decrease of transgene expression induced in the paraventricular nucleus by 72 h fasting. Supplementing the drinking water with 10% glucose increased beta-galactosidase expression both in the paraventricular nucleus and arcuate nucleus of control mice. Finally, none of the treatments altered transgene expression in the dorsomedial hyphothalamic, ventromedial, and amygdaloid nuclei. Results suggest that changes in energetic balance affect Y(1) receptor expression in the paraventricular and arcuate nuclei and that leptin regulates the NPY-Y(1) system in the paraventricular nucleus. Different regulatory signals might modulate the NPY-Y(1) transmission in the dorsomedial hyphothalamic and ventromedial hyphothalamic nuclei.
Subject(s)
Fasting/physiology , Gene Expression/drug effects , Gene Expression/physiology , Glucose/pharmacology , Hypothalamus/physiology , Leptin/pharmacology , Receptors, Neuropeptide Y/genetics , Animals , Arcuate Nucleus of Hypothalamus/physiology , Body Weight/drug effects , Body Weight/physiology , Drinking , Lac Operon/physiology , Mice , Mice, Transgenic/genetics , Receptors, Leptin , Receptors, Neuropeptide Y/physiology , Solutions , Transgenes/physiologyABSTRACT
Melatonin has immuno-enhancing properties and exerts colony-stimulating activity (CSA) via T-helper cell-derived opioids. Opioid agonists may mimic the CSA of melatonin with an order of potency that suggests the presence of a type 1 kappa-opioid receptor (type 1 kappaOR [kappa]-OR]). The kappaOR antagonist nor-binaltorphimine neutralized the in vitro effect of melatonin and inhibited regeneration of hematopoiesis in mice treated with carboplatin. The CSA of dynorphin A was abolished by incubation of adherent cells with antisense (AS) oligodeoxynucleotide to kappaOR or by addition of anti-interleukin (IL)-1 monoclonal antibody (mAb), which also neutralized the effect of melatonin. Bone marrow cells that express kappaORs were identified to be macrophages. In conclusion, we describe the presence of kappaORs in bone marrow macrophages and suggest a hematopoietic function for melatonin via endogenous kappa-opioid agonists and, possibly, IL-1.
