By investigating hypothalamo-pituitary-adrenal (HPA) neuropeptide responses to maternal separation during infancy in the rat, we hope to develop neuroendocrine markers for early identification of children experiencing significant familial stress, and who may be at risk for developing depression. During infancy, the rat HPA axis activity is regulated by the mother. Acute separation from the mother increased serum corticosterone. Subsequent maternal contact quickly reversed this response. Repeated separations from the mother during the first two weeks of life permanently desensitized the HPA axis to stimulation. We have observed that oxytocin (OXT) and corticotropin releasing factor (CRF) stimulated corticosterone secretion during infancy. The magnitude of the stimulation was dependent upon maternal separation. It is hypothesized that acute and repeated separation induced changes in CRF and OXT concentrations. We will measure the levels of CRF and OXT by radioimmunoassay in cell body and terminal areas of infant rat brain following acute or repeated maternal separation (Study 1). To test the hypothesis that the concentration of adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone (alpha-MSH) may also flucuate with separation state, we will measure the levels of these hormones by radioimmunoassay in pituitary and serum following acute and repeated maternal separation, and in response to CRF and OXT administration (Study 2). To distinguish the relative contributions of CRF and OXT to the corticosterone-releasing potency of acute maternal separation, we will administer specific CRF or OXT antibodies to pups exposed to acute maternal separation with and without CRF or OXT administration (Study 3). HPA axis desensitization following repeated maternal separation may be dependent upon increased CRF and OXT inhibition by corticosterone negative feedback mechanisms. We will attempt to block the repeated separation effect by administering the corticosterone antagonist, RU-486 (Study 4). Desensitization of the HPA axis to stress as a result of repeated maternal separation persists into adulthood. We hypothesize that adult rats that have been repeatedly separated as infants will exhibit reduced corticosterone responsiveness to OXT and CRF under stressed and non- stressed conditions (Study 5).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH046442-04
Application #
3475437
Study Section
Psychobiology and Behavior Review Committee (PYB)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1993-05-01
Budget End
1994-03-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Johns, J M; Noonan, L R (1995) Prenatal cocaine exposure affects social behavior in Sprague-Dawley rats. Neurotoxicol Teratol 17:569-76
Noonan, L R; Caldwell, J D; Li, L et al. (1994) Neonatal stress transiently alters the development of hippocampal oxytocin receptors. Brain Res Dev Brain Res 80:115-20