Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 124-142). Also available on the Internet.

Thesis (M.Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 109-144) Also available in print.

Thesis (Ph. D.)--Case Western Reserve University, 2005. / [School of Medicine] Department of Pharmacology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 87-114).

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Lactation is the final stage of reproduction in mammals and is characterized by chronically elevated prolactin and suppressed luteinizing hormone. The neuroendocrine regulation of prolactin and luteinizing hormone during lactation are not fully understood. In the hypothalamic arcuate nucleus is a population of neurons known as KNDy neurons because they co-express the neuropeptides Kisspeptin, Neurokinin B and Dynorphin. These neurons are known to project to gonadotropin-releasing hormone cell bodes in the preoptic area and nerve terminals in the median eminence, which regulate the secretion of luteinizing hormone, and to dopaminergic tuberoinfundibular neurons in the arcuate nucleus, which are known to regulate prolactin. Because KNDy neurons project to neuronal populations known to regulate both prolactin and luteinizing hormone, the general hypothesis for these studies is that neuropeptides Kisspeptin, Neurokinin B and Dynorphin play a role in regulating these hormones or are regulated by these hormones during lactation. In a model of lactating rats deprived of their pups for 24 hours, intracerebroventricular injection of an endogenous Kisspeptin receptor ligand, Kp-10, modestly increased prolactin secretion and markedly increased luteinizing hormone secretion. Neither Neurokinin B nor the Neurokinin B receptor agonist, Senktide, had a significant effect on either hormone in this rat model. Dynorphin and U-50,488, a kappa opioid receptor agonist, robustly increased prolactin although no changes were measured in luteinizing hormone levels. In this model of 24-hour pup-deprived lactating rats, prolactin was responsive to kappa opioid receptor agonists and luteinizing hormone was responsive to Kisspeptin receptor agonists. In a second set of experiments, sense and anti-sense in situ hybridization probes were developed for Kiss1, the Kisspeptin gene, and Tac2, the gene encoding Neurokinin B. It was confirmed that the cDNA sequences cloned for these mRNAs were correct and were highly homologous to published rat mRNA sequences. In situ hybridization was performed using the Kiss1 and Tac2 probes, as well as a probe for Pdyn, which encodes Dynorphin. No specific cytoplasmic signal was observed using any of the three sense probes. With the anti-sense probes, clusters of reduced silver grains representing Kiss1, Tac2 and Pdyn mRNAs were observed in the arcuate nucleus, lateral to the third ventricle and superior to the median eminence. These expression patterns were consistent with the published literature. Also, the expression patterns for all three neuropeptides were similar to each other, suggesting that many of the arcuate nucleus neurons lateral to the third ventricle and superior to the median eminence are KNDy neurons.

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Atrial natriuretic peptide (ANP) of atrial myocyte origin, has been shown to play a role in the diuresis, natriuresis, and antagonism of angiotensin and vasopressin. However, it is now apparent that in addition to the production of the peptide in the heart and in its role in fluid and electrolyte homeostasis, it is also produced in the central nervous system participating in the regulation of pituitary hormone secretion. Administration of ANP through both central and peripheral routes has been shown to inhibit secretion of luteinizing hormone (LH) in the gonadectomized rat model. A better understanding of the modulatory role of ANP on LH secretion and its possible mechanisms will add to our knowledge of the effects of neuropeptides on reproductive function. Brain natriuretic peptide (BNP) is a bioactive peptide of 26 amino acid residues recently identified in porcine brain. The peptide exerts potent diuretic-natriuretic and vasorelaxant effects, in a manner similar to that of ANP. BNP has a remarkable high sequence homology to ANP, especially in the 17 amino acid ring formed by an intramolecular disulfide linkage which is required for biological activity. The presence of BNP with ANP in the mammalian brain and remarkable resemblance in their molecular structures and physiological functions implies that BNP may also exert an inhibitory effect on LH secretion like ANP. This research focused on the effects of centrally administered ANP and BNP on pulsatile LH secretion and their possible mechanisms of action in ovariectomized rats. After third ventricle infusion of ANP or BNP, inhibition of mean plasma LH level, LH pulse amplitude and pulse frequency was observed. In searching for the possible mechanisms of inhibitory effect of ANP or BNP on pulsatile LH secretion, the effect of inhibiting the endogenous opiate system with naloxone on the action of centrally administered ANP or BNP was tested. Application of naloxone reversed the inhibitory effect of ANP and BNP on mean plasma LH level and LH pulse amplitude, but in terms of pulse frequency, naloxone treatment failed to reverse the inhibitory effect of ANP or BNP. In separate experiments, pretreatment with pimozide, a dopaminergic receptor blocker, prevented the inhibitory action of ANP and BNP on LH secretion. After infusion of ANP or BNP, there were no significant decrease in mean plasma LH level, pulse amplitude and pulse frequency in the pimozide-pretreated rats. In summary, the present study shows that both ANP and BNP inhibit pulsatile LH secretion, suggesting that the inhibitory effects on LH secretion once thought to be mediated by ANP alone may be regulated through a dual mechanism involving both ANP and BNP. Furthermore, the inhibitory mechanisms may involve the interactions of ANP and BNP with central opiate system and dopaminergic system on LH secretion. / Medicine, Faculty of / Obstetrics and Gynaecology, Department of / Graduate

Four experiments were conducted to investigate the effect of naloxone, an opioid receptor antagonist, on pituitary LH secretion in Holstein cows during two periods after parturition and two phases of the estrous cycle. In experiment 1, 24 cows (12 primiparous; 12 multiparous) received either saline (n = 12) or 1 mg/kg naloxone (n = 12) i. v. at 14 1 days postpartum. Blood samples were collected at 15-minute intervals for 2 hours before and 2.5 hours after naloxone or saline. Serum LH concentrations increased (P < .05) in response to naloxone injection in both primi- and multiparous cows. Saline injection did not affect LH concentrations. In experiment 2, 27 cows (13 primiparous; 14 multiparous) received either saline (n=14) or 1 mg/kg naloxone (n=13) i. v. at 28 ± 1 days postpartum. Blood samples were collected as in the previous experiment. Naloxone did not affect serum LH concentrations in either primi- or multi-parous cows at 28 days postpartum. In experiment 3, estrous cycles were synchronized via prostaglandin administration (25 mg) in 22 cows (10 primiparous; 12 multiparous). Cows received either saline (n=11) or 1 mg/kg naloxone (n=11) Lv. during the luteal phase of the estrous cycle. Blood samples were collected as in the previous experiments. Luteinizing hormone concentrations were not affected by naloxone in either primi- or multi-parous cows during the luteal phase of the estrous cycle. In experiment 4, the same cows used in experiment 3 received a second dose of prostaglandin (25 mg). Thirty-six hours later, during the follicular phase of the estrous cycle, the cows received either saline (n =9) or 1 mg/kg naloxone (n = 11) i. v. Naloxone increased (P < .05) serum LH concentrations in both primi- and multi-parous cows in the follicular phase. These results suggest that LH release in the early postpartum dairy cow is regulated, at least in part, by endogenous opioid pep tides , and the ability of naloxone to affect LH secretion may change as days postpartum increases, perhaps due to changes in degree of inhibition by endogenous opioid peptides, and (or) changes in serum progesterone concentration due to onset of ovarian activity during postpartum period. It appears that the modulation of LH secretion may be mediated via opioids during the follicular phase of the estrous cycle. However, an opioid-mediated mechanism for modulation of LH secretion was absent or overridden by progesterone feedback during the luteal phase of the estrous cycle. / Master of Science