Arthur J. Prange, Jr. - US grants

In the laboratory, work will be addressed to three endogenous neuropeptides, oxytocin (OXY), neurotensin (NT) and thyrotropin-releasing hormone (TRH). Work with OXY will focus on the property of this peptide to produce maternal behavior in virgin female rats. Interest is now focused on blocking the action of endogenous OXY in triggering this behavior in a variety of circumstances. Neurotensin is of interest because many of its actions run parallel to those of neuroleptic drugs. We propose to identify the sites in brain where NT enhances pentobarbital-induced sleeping time and where it enhances pentobarbital-induced hypothermia. Additional studies bear upon the role of NT in thermoregulation. While NT prolongs pentobarbital-induced sleeping time, TRH shortens it. We will use this property of TRH to study the action of putative inhibitors of TRH synthesis and inhibitors of TRH degradation. Additional studies are addressed to probable interactions between TRH and NT. In the clinic, work will focus on three endogenous peptides: NT, TRH, and insulin. Because NT can blunt the TSH response to TRH it will be of interest to discern whether patients with blunted responses have altered levels of NT in spinal fluid. The TSH response to TRH will also be studied as regards its characteristics in a large population of normals and its possible influence by stage of the menstrual cycle. Its possible value in predicting the efficacy of L-triiodothyronine as an adjunct to imipramine in depression will also be studied. The behavioral and endocrine effects of insulin will be studied in normal subjects and schizophrenic patients while hypoglycemia is prevented by glucose administration. These studies are prompted in part by recent observations that not all endocrine effects of insulin are due to hypoglycemia. This broad program of research into the behavioral and predictive properties of peptide hormones in both animals and man will involve a variety of techniques and a number of collaborators skilled in their special application.

We have reported that intracerebroventricular administration of oxytocin to virgin female rats induces a high incidence of rapid-onset full maternal behavior. The incidence of maternal behavior is dose related. Extensive specificity studies have shown that, in addition to oxytocin, arginine vasopressin and tocinoic acid (the ring structure of oxytocin) induce a lesser, though statistically significant, rate of full maternal behavior. Prostaglandin F2alpha induces transient partial maternal behavior. Many substances are inactive. The rapid induction of maternal behavior, full or partial, by active substances appears to be estrogen dependent. Thus our work is addressed to the triggers of maternal behavior as contrasted to the endocrine permission of such behavior. Our work, centered on peptides, complements earlier elegant descriptions of the role of steriod hormones. We propose to investigate the importance of brain release of endogenous oxytocin and arginine vasopressin th the onset of maternal behavior in parturient rats and to the maintenance of maternal behavior in nursing rats. We will assess the impact on onset and maintenance of maternal behavior of manipulations that deplete extra hypothalamic brain sites of oxytocin and vasopressin (lesioning of the paraventricular nucleus and/or the suprachiasmatic nucleus). For the same dependent variables we will assess the impact of manipulations that prevent oxytocin and vasopressin from interacting with receptors (intracerebroventricular injection of oxytocin- and vasopressin-directed antisera or infusion of competitive inhibitor analogs of these peptides). We propose to measure regional brain content and CSF and blood levels of oxytocin and arginine vasopressin and brain uptake of [3H] oxytocin in female rats in hormonal states either conducive or inimical to the onset of maternal behavior and in nursing and post nursing rats that have given birth. We intend to determing the loci at which oxytocin and arginine vasopressin have their maternal behavioral effects by injecting these peptides into selected brain sites.

The overall goal of this Center is to establish an organization for the neuropsychoendocrinological study of the major mental disorders of adults and children which form the hard core of mental health problems. In adults these include depession, mania, alcoholism, schizophrenia and the mental syndromes associated with renal dialysis; in children, hyperkinesis, autism, and mental retardation. The theoretical base for these studies consists of the principles of neuroendocrinology and the principles of neurotransmitter physiology. A pituitary response fault (diminished TSH response to TRH) has been identified in some depressed patients and in some conditions the fault is related to the state of illness or to the trait of being at high risk for these illnesses. Parallel pituitary response testing, with TRH, is carried out in psychotic and hyperkinetic children. Related neuroendocrine investigations are addressed to renal dialysis patients who show characteristic mental syndromes. In adult schizophrenia there is dissociation between these axes; TSH response appears to be positively related to baseline cortisol values. In normal controls and in all other diagnostic groups the relationship is negative. The altered relationships may provide a biochemical marker for schizophrenia. The techniques of modern genetics are used to explore relationships between affective disorders and alcoholism and hyperkinetic syndrome. Relatives of probands who show TSH blunting are tested to establish whether the physiological fault is a marker in families for the demonstration of illness. Four disciplines of basic science are brought to bear on problems relevant to clinical goals. These are biochemistry, animal neuroendocrinology, animal psychopharmacology, and peptide behavioral pharmacology. Work in these areas clarifies problems of clinical origin; it also provides findings that suggest clinical intervention. The nexus of related clinical and basic projects provide a basis for rich training and practical experiences for several categories of trainees.

This application seeks continuation support for a NIMH CRC dedicated to the study of major mental disorders of adults and children. In adults these include depression, mania, alcoholism, panic disorder and schizophrenia; in children (or young adults), the sequelae of closed head injury. The theoretical base for the proposed studies consists largely of the principles of neuroendocrinology and psychoendocrinology; also employed are the principles of neurotransmitter physiology, pharmacodynamics and kinetics, immunology, neuropsychology, biostatistics, life history and computer science. Two endocrine faults--the reduced TSH response to TRH and the failure to suppress cortisol after dexamethasone--provide foci for the organization of several proposed clinical studies. Other conceptual themes are: neuroleptic metabolism in schizophrenic patients; responses of depressed and manic patients to drugs that alter cholinergic function; serotonin function in affective disorders. Two studies explore totally new ground: is hypoglycemia necessary to the behavioral effects of insulin; given a tantalizing biochemical relationship, how do chlordiazepoxide and TRH interact on behavior and endocrine function? A study, epidemiologic in design and scheduled to precede others in performance, assesses the incidence and significance of marginal hypothyroidism in psychiatric inpatients. The effects of psychostimulants on patients with late consequences of closed head injury will also be studied. The Center's four basic science sections (one is new) are tied in various ways to each other and to the five clinical sections (two are new). Several studies focus on the HPT axis: with importance for peptide physiology generally, how is TRH synthesized; how do TRH and cholinergic systems interact in a model of depression (Porsolt test); does even slight hypothyroidism increase memory loss in rats after ECT? Some animal studies explore the utility of peptides as markers of adrenergic or cholinergic activity and the effects early separation on later HPT and HPA function. Other studies resonate with our developing interest in schizophrenia: changes in DA metabolism during the reproductive cycle; the effects of gonadal steroids on DAergic activity; the effects of diabetes on DA receptor functions. Six core groups (three are new) support the clinical and basic science sections and enhance each other's work. Teaching and training activities of the Center have increased in parallel with the depth and span of research activities.

This application seeks funding for the 14th to 18th years, inclusive, of the NIMH CRC at UNC-Chapel Hill. The requested funds would allow the CRC to continue its evolution as a core-based center and to continue to strengthen its research in the cause and treatment of major mental disorders. These include mood disorders, alcoholism, anxiety disorder, schizophrenia, movement disorders, and the neural and mental consequences of HIV infection. The theoretical base for the proposed research is founded in psychoendocrinology. However, as interest and opportunity have allowed, the base has extended to other disciplines. Research is performed through the agency of five scientific programs: the Psychoendocrinology Program; the Psychopharmacology Program; the Psychoimmunology Program; the Psychophysiology Program; the Reproductive and Developmental Psychobiology Program. Each program consists of a set of interlocking relationships; some of these form bridges between programs. The work of the scientific programs and of selected start-up projects is supported by eight core groups; the Administrative Core; the Clinical Research Support Core; the Neurobehavioral Assessment Core; the Endocrine Assay Laboratory; the Psychoneuroimmunology Laboratory; the Bioanalytical Laboratory; the Data Management and Biostatistics Core; the Computer Support Core. Only the Neurobehavioral Assessment Core is new. It was nurtured within the Clinical Research Support Core until it had demonstrated its viability and its importance to the Center and was then split off. An outstanding asset of the Center is the Clinical Research Unit at Dorothea Dix Hospital, where patients can be housed for intensive and extensive study at no cost to the federal government. This facility, the wards of the Department of Psychiatry, and the General Clinical Research Center at UNC offer an outstanding nexus of opportunities for clinical investigations in psychiatric inpatients, outpatients, selected medical population, and health volunteers. The Administrative Committee within the Administrative Core is the main executive unit of the Center. It interfaces with the cores and the scientific programs on the one hand and on the other hand with the Department of Psychiatry, Dix Hospital, the General CRC and the Advisory Board of the Center. The Advisory Board, the Administrative Committee and all Center members meet in a full-day off-campus retreat each November. The Center has a major investment in training as well as in research. This has been enormously advanced by the funding in the UNC Department of Psychiatry of a NIMH Clinical Research Fellowship Training grant, in 1988.

This application seeks funding for the 14th to 18th years, inclusive, of the NIMH CRC at UNC-Chapel Hill. The requested funds would allow the CRC to continue its evolution as a core-based center and to continue to strengthen its research in the cause and treatment of major mental disorders. These include mood disorders, alcoholism, anxiety disorder, schizophrenia, movement disorders, and the neural and mental consequences of HIV infection. The theoretical base for the proposed research is founded in psychoendocrinology. However, as interest and opportunity have allowed, the base has extended to other disciplines. Research is performed through the agency of five scientific programs: the Psychoendocrinology Program; the Psychopharmacology Program; the Psychoimmunology Program; the Psychophysiology Program; the Reproductive and Developmental Psychobiology Program. Each program consists of a set of interlocking relationships; some of these form bridges between programs. The work of the scientific programs and of selected start-up projects is supported by eight core groups; the Administrative Core; the Clinical Research Support Core; the Neurobehavioral Assessment Core; the Endocrine Assay Laboratory; the Psychoneuroimmunology Laboratory; the Bioanalytical Laboratory; the Data Management and Biostatistics Core; the Computer Support Core. Only the Neurobehavioral Assessment Core is new. It was nurtured within the Clinical Research Support Core until it had demonstrated its viability and its importance to the Center and was then split off. An outstanding asset of the Center is the Clinical Research Unit at Dorothea Dix Hospital, where patients can be housed for intensive and extensive study at no cost to the federal government. This facility, the wards of the Department of Psychiatry, and the General Clinical Research Center at UNC offer an outstanding nexus of opportunities for clinical investigations in psychiatric inpatients, outpatients, selected medical population, and health volunteers. The Administrative Committee within the Administrative Core is the main executive unit of the Center. It interfaces with the cores and the scientific programs on the one hand and on the other hand with the Department of Psychiatry, Dix Hospital, the General CRC and the Advisory Board of the Center. The Advisory Board, the Administrative Committee and all Center members meet in a full-day off-campus retreat each November. The Center has a major investment in training as well as in research. This has been enormously advanced by the funding in the UNC Department of Psychiatry of a NIMH Clinical Research Fellowship Training grant, in 1988.