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Abstract the ROLE of ESTROGEN in ORPHANIN FQ/NOCICEPTIN INDUCED PROLACTIN RELEASE by Prajakta Dinesh Mangeshkar the Role of Estr

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Abstract the ROLE of ESTROGEN in ORPHANIN FQ/NOCICEPTIN INDUCED PROLACTIN RELEASE by Prajakta Dinesh Mangeshkar the Role of Estr Abstract THE ROLE OF ESTROGEN IN ORPHANIN FQ/NOCICEPTIN INDUCED PROLACTIN RELEASE By Prajakta Dinesh Mangeshkar The role of estrogen in modulating the prolactin secretory response to Orphanin FQ/Nociceptin (OFQ/N) and the involvement of hypothalamic dopaminergic neurons in mediating this response were investigated. The prolactin secretory response to OFQ/N was significantly attenuated in placebo treated female Sprague-Dawley rats compared to estrogen replaced animals. Also, OFQ/N produced a significant decrease in the phosphorylated tyrosine hydroxylase (pTH) to hydroxylase (TH) ratio only in estrogen treated rats, indicating inhibition of hypothalamic dopaminergic neurons. Estrogen treatment produced a significant decrease in pituitary ERα expression levels, but sensitivity to OFQ/N was still higher than in placebo animals. In the hypothalamus, there were several protein bands that may be isoforms of ERα. These results indicate that estrogen is necessary for the prolactin secretory response to OFQ/N in female rats and that OFQ/N suppresses hypothalamic dopaminergic activity only in the presence of estrogen. THE ROLE OF ESTROGEN IN ORPHANIN FQ/NOCICEPTIN INDUCED PROLACTIN RELEASE A Thesis Submitted to the faculty of Miami University in partial fulfillment of the requirements for the degree of Master of Science Department of Zoology by Prajakta Dinesh Mangeshkar Miami University Oxford, OH 2005 Advisor: _______________________________________ Dr. James Janik Co-Advisor: ________________________________________ Dr. Phyllis Callahan Reader: ________________________________________ Dr. Kathy Killian Reader: _________________________________________ Dr. Paul Harding Table of Contents INTRODUCTION Prolactin and its Regulation 1 Tyrosine Hydroxylase 1 Gender Differences 2 Role of Ovarian Steroids 3 Endogenous Opiates 5 Orphanin FQ/Nociceptin 5 Orphanin FQ/Nociceptin and Prolactin Release 6 MATERIALS AND METHODS Animals and Treatment 10 Western Blot Analysis 11 Hormone Assays 12 Statistical Analysis 12 RESULTS Effects of Treatment on plasma 17-β estradiol, wet uterine weights and body weights 13 Effect of Estrogen on OFQ/N induced PRL release 13 Hypothalamic pTH and TH expression levels 13 Effect of estrogen on ERα protein expression in the pituitary and hypothalamus 14 DISCUSSION 30 REFERENCES 34 ii List of Tables TABLE 1. Effects of estrogen on body weight in ovx/placebo and ovx/estrogen female rats. 18 iii List of Figures FIGURE 1. Plasma 17-β estradiol levels and uterine weight of ovx/estrogen and ovx/placebo animals. 15 FIGURE 2.The effect of estrogen on OFQ/N induced prolactin secretion in ovx female rats. 19 FIGURE 3. The effect of estrogen replacement on hypothalamic pTH and TH levels and on the pTH: TH ratio. 21 FIGURE 4. The effect of OFQ/N administration on hypothalamic pTH and TH levels and on the pTH:TH ratio. 23 FIGURE 5. The effect of OFQ/N on pTH and TH expression levels on the pTH:TH ratio in ovx/estrogen treated animals. 25 FIGURE 6. The effect of estrogen on ERα in ovx female rats. 27 iv 1. Introduction and Background Prolactin and its Regulation: Prolactin (PRL) is a polypeptide hormone, composed of 197-199 amino acids and has a molecular weight of 23kDa (Goffin et al, 2002). Prolactin plays a major role in the maintenance and stimulation of the mammary gland during lactation, as well as the regulation of a number of diverse physiological processes including homeostasis, growth, reproduction and metabolism (Neill and Nagy, 1994; Goffin et al, 2002). Prolactin is primarily secreted by the lactotropic cells of the anterior pituitary gland (Goffin et al, 2002). Prolactin secretion is affected by a number of factors, but is primarily under the tonic inhibitory control of hypothalamic dopamine (Freeman et al, 2000). The dopamine (DA) perikarya, which are located in the periventricular (A14) and arcuate nuclei (A12) of the hypothalamus, provide dopamine to the pituitary (Moore and Lookingland, 1995). These neuronal populations are divided into three systems: the tuberohypophysial dopaminergic (THDA) neurons project from the rostral portion of the arcuate nucleus to the intermediate and neural lobes of the pituitary; the periventricular-hypophysial dopaminergic (PHDA) neurons project from the periventricular nucleus to the intermediate lobe of the pituitary; and the tuberoinfundular dopaminergic (TIDA) neurons project their short axons from the dorsomedial arcuate nucleus to the median eminence of the hypothalamus and release DA into hypophysial portal vessels (Moore and Lookingland, 1995; Freeman et al, 2000). Among these neuronal populations, the TIDA neurons are the major regulators of prolactin secretion (Reymond and Porter, 1985; Moore and Lookingland, 1995; Freeman et al, 2000). Dopamine travels, via the portal system, to the anterior lobe of the pituitary gland, binds to pituitary D2 receptors and, through the action of Gi proteins, leads to inactivation of the voltage-gated calcium channels. This tonically inhibits prolactin release from secretory granules, and it also inhibits adenylyl cyclase which suppresses PRL gene expression (Neill and Nagy, 1994; Ben-Jonathan and Hnasko, 2001). Tyrosine hydroxylase: Tyrosine hydroxylase (TH) is the rate –limiting enzyme in the biosynthesis of 1 catecholamines (Ikeda et al, 1965; Kumer and Vrana, 1996). TH has a molecular weight of 60kD and occurs as a tetramer, composed of a regulatory N- terminal and catalytic C- terminal region (Campbell et al, 1986, Grennet et al, 1987, Haycock, 1990). Because TH plays a pivotal role in numerous physiological processes, its synthesis is tightly regulated by a number of different factors. The two primary forms of regulation include long- term regulation, involving changes in gene expression, and short – term regulation, involving phosphorylation by different protein kinases (Kumer and Vrana, 1996). Phosphorylation is a generally accepted form of TH activation in vivo (Kaufman 1995) and sites of phosphorylation have been identified on the TH 40 amino acid N-terminal (Haycock et al, 1990). These include four serine sites: Ser8, Ser19, Ser31 and Ser40. Of these four sites, phopshorylation of Ser40 is known to have a major effect on TH activity (Kumer and Vrana, 1996). Recent evidence suggests that the phosphorylation of Ser40 and Ser19 residues results in an open conformation of the TH molecule and that phosphorylation of Ser19 leads to an increase in the rate of Ser40 phosphorylation (Bevilaqua, et al, 2001). The residues around Ser40 (Arg-Arg-Gln-Ser40-Leu) are known to be commonly recognized by PKA, PKC and Cam-PKII (Kumer and Vrana, 1996). TH is a non-heme iron protein which exists in two forms, ferric and ferrous (Ramsey et al, 1996). Tetrahydropterins activate TH by reducing the ferric to a ferrous form (Ramsey et al, 1996). Cathecholamines like dopamine and dihydroxyphenylalanine (DOPA) can bind to the ferric form and trap it in an inactive form (Ramsey and Fitzpatrick, 2000). However, it has been suggested that the primary effect of phosphorylation at Ser40 is a decrease in the enzyme’s affinity for catecholamines (Ramsey and Fitzpatrick, 1998, 2000). Thus, phosphorylation activates the enzyme by increasing the rate of dissociation of bound catecholamines allowing reduction to the ferrous form to proceed. Because TH phosphorylation represents the activity of the enzyme, and therefore dopamine synthesis, its regulation by OFQ/N and ovarian steroids is a focus of this study. Gender Differences: There are fundamental sexual differences in the activity of the TIDA neurons that influence prolactin regulation (Gunnet and Freeman, 1982). Although the concentrations of dopamine 2 and the density of the TIDA neurons are similar in males and females (Arbogast and Voogt, 1990), there are sexual differences in TIDA neuronal activity and responsiveness. Dopamine synthesis and turnover in the median eminence of female rats is 6-8 times higher than in male rats (Gudelsky and Porter, 1981). This sex-related difference is not a function of the suppressive effect of androgens, but rather a stimulatory effect of the ovarian steroids (Gudelsky and Porter, 1981). Females have higher TH mRNA levels in the arcuate nucleus (Arbogast and Voogt, 1990), as well as higher concentrations of TH in the median eminence (Porter, 1986). This greater expression of the TH gene in females could account for the higher TH activity in the TIDA neurons (Arbogast and Voogt, 1990). TH activity in females is decreased by ovariectomy and restored by estrogen, however, in males, the reverse occurs; TIDA neuronal activity is increased by orchidectomy and decreased by testosterone (Ben- Jonathan and Hnasko, 2001). Thus, these differences in the TIDA neuronal activity between male and female rats can be attributed to the steroid environment and the modulation of these neurons by the ovarian steroids. Role of Ovarian Steroids: Estrogen (E) has direct physiological effects on hypothalamic neurons and pituitary cells. Estrogen has both positive and negative effects on the pituitary (for review see Shupnik et al, 2002). In lactotroph cells, E has been shown to stimulate prolactin synthesis and secretion (Lieberman et al, 1981; Scully et al, 1997). Administration of chronic estradiol, alone or in combination with progesterone, modulates the responsiveness of lactotrophs to dopamine by increasing the proliferation and percentage of PRL secreting lactotrophs (Livingstone et al, 1998). Further, estradiol also causes an increase in PRL-receptor (PRL-R) expression in the dorso-medial
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