Craig Alan Johnston, Ph.D. - US grants

Many neuropeptides originally isolated from the gastrointestinal system are also synthesized in the brain. Several of these "Brain- Gut" peptides have been shown capable of influencing the secretion of reproductive hormones from the anterior pituitary. Indeed, one of the major foci at recent meetings concerning the basic and clinical functions of these peptides, individually, has been their possible role in neuroendocrine regulation. Although the hypothesis that these centrally-derived peptides may play ar important role in neuroendocrine regulation is becoming widely accepted, the sites and mechanisms by which that regulation is exerted is poorly understood. Furthermore, elucidating the interactions occurring between these individual peptides as well as between central neurotransmitters and these peptide systems may be critical toward understanding the mechanisms of action by which these peptides exert their influence on reproductive hormone secretion. Therefore, the objectives of the proposed conference are to allow experts on the reproductive neuroendocrine functions of each individual "Brain-Gut" peptide to present a summary of recent advances concerning their particular peptide area, and to benefit from the insights provided by experts working with different peptides in attempting to formulate hypotheses about the participation of these peptides in reproductive neuroendocrine control.

Travel funds are provided to bring a group of 12 distinguished lecturers to a meeting on "Brain.gut Peptide Regulation of Reproductive Hormone Secretion" to be held at Washington State University in Pullman, Washington. The meeting involves approximately 150 participants representing a large geographical distribution. The renowned lecturer will present a summary of recent advances concerning their particular peptide area emphasizing its role in the regulation of reproductive neuroendocrine function. The objective is to integrate the presentations to formulate hypotheses about the sites and mechanisms of action/interactions of these neuropeptide s in carrying out their regulatory action. The results and discussion will provide important information concerning the central mechanisms of neuroendocrine regulation and will define clear directions for future research in this area. This valuable information could lead towards the development of novel therapeutic regimens for treating clinical reproductive dysfunctions associated with aberrant reproductive hormone secretion. The proceedings from the meeting will be published in a book. ***

The long-term goal of this research project is to characterize the nature, manner, mechanisms and site(s) of action by which central oxytocin (OXY) neurons regulate the release of luteinizing hormone releasing hormone (LHRH) and luteinizing hormone (LH) on the afternoon of proestrus in the cycling female rat. Recent evidence by our laboratory suggests that central OXY neurons may exert a physiologically important stimulatory influence on the release of LHRH and LH occurring just prior to ovulation on the afternoon of proestrus in the cycling female rat (when estradiol levels are physiologically high). The present proposal will test the hypothesis that the stimulatory influence of central OXY neurons on LHRH and LH release is physiologically relevant and depends upon the presence of high levels of plasma estradiol. We will examine the ability of passive immunization against OXY or specific OXY antagonists to affect basal and stimulated levels of plasma LH as well as LHRH content and release occurring on the afternoon of proestrus. We will evaluate the ability of centrally administered OXY to affect LH secretion as well as LHRH content and release on proestrus (when estradiol levels are physiologically high) compared with metestrus (when plasma estradiol is low). The ability of pretreatment with OXY or LHRH antagonists to prevent the OXY-induced effects on plasma LH will be examined in order to demonstrate that the central action of OXY on LH secretion is mediated by LHRH neurons. Finally, we will investigate possible interactions between other physiologically relevant LHRH secretagogues and OXY in regulating LHRH/LH release, and the influence of plasma estradiol levels on their expression, by examining on proestrus and metestrus 1) the ability OXY antagonism to prevent changes in LH caused by the central injection of these secretagogues, and 2) the ability of administration of antagonists or passive immunization against the secretagogues to affect the changes in LH/LHRH release caused by the central injection of OXY. The knowledge gained from these studies should advance our basic understanding concerning the nature, sites, mechanisms and physiological significance of OXY in regulating the preovulatory surge of LH, permit the development of dynamic tests to characterize and diagnose the nature of central causes responsible for the aberrant secretion of LH, and provide insight toward the development of possible novel therapeutic regimens to either alleviate clinical dysfunctions resulting from the abnormal secretion of LH or to cause contraception.

The long-term goal of this research program is characterize the manner, mechanisms and site(s) of action by which the neurointermediate pituitary lobe (NIL) influences the secretion of adrenocorticotropin (ACTH) and prolactin (PRL) from the anterior pituitary (AP). Recent studies demonstrate that the surgical removal of the NIL in vivo (NIL-X) significantly and selectively influences the dynamic secretion of ACTH and PRL from the AP. However, very little is known concerning the factor(s), mechanisms(s) and site(s) of action by which this influence of the NIL on AP hormone secretion is exerted. The present proposal will test the hypothesis that the NIL influences ACTH and PRL secretion both by modifying the sensitivity of the AP to respond to known, physiologically relevant releasing-(RF) and release-inhibiting factors (RIF) for the hormones, ACTH and PRL, and by interacting with the brain in a feedback manner to regulate the concentrations and release of RF/RIF involved in ACTH and PRL secretion. The in vivo ACTH and PRL secretory responses to RF/RIF will be evaluated at acute (16 hr) and intermediate (12 day) and chronic (28 days) time points following NIL-X or sham operations in freely moving, unanesthetized rats. The ability of NIL-X to affect the concentrations, synthesis, and release of physiologically relevant RF/RIF in the brain will be evaluated using specific radioimmunoassays, in situ hybridization techniques, and HPLC coupled with electrochemical detection. In addition, if the sensitivity of the AP hormonal response to RF/RIF stimulus or the concentration/synthesis/release of central RF/RIF is determined to be altered by NIL-X, then additional studies will examine which of these NIL-X induced effects are due to the removal of oxytocin (OXY) and/or arginine- vasopressin (AVP) secreting nerve terminals located within the NIL: the ability of replacement therapy with OXY and/or AVP to reverse the NIL-X- induced effects as well as the ability of chronic treatment with potent AVP and/or OXY antagonists to induce changes, similar to those observed following NIL-X will be examined. The knowledge gained from these studies should not only advance greatly our basic scientific knowledge concerning the neuroendocrine regulation of ACTH and PRL secretion from the AP, but should also permit the development of dynamic tests to characterize and diagnose the nature of underlying causes responsible for the abnormal secretion of ACTH and PRL, and provide insight toward the development of possible novel therapeutic regimens for the alleviation of clinical dysfunction resulting from the abnormal secretion of ACTH and PRL.

biomedical equipment purchase;

biomedical equipment purchase;