Oxytocin(OT) is a nonapeptide that functions as both a hormone and a neuropeptide during certain reproductive processes and behaviors. OT is essential for milk ejection during lactation, enhances uterine contractility at parturition and induces maternal behavior in the rat. Maternal behavior in most mammals is stimulated by the hormonal milieu of late pregnancy. In the rat, rising levels of estrogen (E) superimposed on the late-term decline in progesterone (P), stimulate maternal behavior. The ovarian steroid exposure which optimally stimulate maternal behavior (declining P in the setting of E priming) also enhances levels of oxytocin (OT) mRNA and OT peptide in the paraventricular and supraoptic nuclei (PVN and SON) of the hypothalamus, which are the sites of synthesis of over 95% of the OT formed within the CNS. Progesterone plays a key role in the regulation of both maternal behavior and OT expression by mechanisms which are not well understood. P can affect neuronal transmission by binding to its cognate nuclear receptor (PR), which acts as a hormone- dependent transcription factor, or by binding to the membrane bound GABAA receptor complex. We hypothesize that changes in OT expression in the PVN and SON of the steroid-treated and pregnant rat are regulated by P-mediated plasticity in subunits of the GABAA receptor and/or by alterations in concentrations of neurosteroids. Increased OT expression within magnocellular and/or parvocellular neurons of the PVN may in turn facilitate the onset of maternal behavior.
The specific aims of this proposal are as follows:1-administer allopregnanolone, or its agonist, ganaxolone, or inhibitors of allopregnanolone formation to the steroid-treated ovariectomized rat and measure changes in OT mRNA and OT peptide in the PVN and SON of the hypothalamus; 2-administer allopregnanolone or its agonist, ganaxolone, or block formation of allopregnanolone and measure indices of maternal behavior, hypothalamic OT mRNA and OT peptide in rats receiving a steroid treatment known to induce maternal behaviors and; 3-measure by in situ hybridization the relative abundance of OT mRNA and GABAA receptor subunit mRNAs and measure by in vitro receptor autoradiography 3[H]muscimol GABAA receptor binding in the hypothalami of the steroid- treated or allopregnanolone (ganaxolone)- treated ovariectomized rat and the pregnant or lactating rat; 4 - administer an antisense oligonucleotide to OT or an OT antagonist i.c.v. to the steroid-treated ovariectomized rat or the pregnant rat and measure indices of maternal behavior and levels of hypothalamic OT mRNA and OT peptide.
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