The main objective of the present study is to elucidate the relationship between the gonadal steroid environment and the organization and function of a steroid-sensitive cholecystokinin (CCK) circuit which is part of a sexually dimorphic limbic- hypothalamic system. This interconnected system, including the medial amygdaloid nucleus, bed nucleus of the atria terminalis, medial preoptic nucleus and the ventromedial region of the hypothalamus, is implicated in the integration of sensory and sex steroid cues involved in the CNS control of reproductive behavior. The sexually dimorphic distribution of the neuroactive peptide CCK in the limbic-hypothalamic system appears to be an important chemical marker for the action of steroids, especially since in this system the mechanism of steroid-regulation of CCK synthesis in males may be different from that in females. Initially, we propose to characterize the interaction between gonadal steroids and the CCK circuit in adult males by determining the metabolite of testosterone necessary to maintain the limbic-hypothalamic CCK circuit. To examine the steroidal influence on CCK release, in vitro superfusion will be utilized. In order to obtain a morphological signature of steroidal action on CCK cells, a combination of steroid autoradiography and CCK- immunohistochemistry will be used to determine if CCK cells in the male concentrate steroids. To begin to elucidate the integration of steroid information within the limbic-hypothalamic system, retrograde tract-tracing will be combined with steroid autoradiography and immunohistochemistry. The role of CCK in the male limbic-hypothalamic system will be tested by injecting CCK into discrete loci in this system. Finally, to understand the organizing-role of gonadal steroids during development, a series of rats will have their perinatal sex-steroid environment altered to produce sex-reversed adults in terms of their reproductive behavior. In two parallel groups of rats, the distribution of CCK- positive cells in the limbic-hypothalamic system of these rats will be determined and correlated with the effects of CCK on reproductive behavior. Together these studies will assess the role of CCK in male copulatory behavior and the effects steroids have on modulating the distribution and release of CCK in male rats. These proposed studies are expected to shed significant light on the important questions of how steroidal information is encoded and integrated in the CNS to influence reproductive behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021220-07
Application #
3402141
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1984-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Sinchak, Kevin; Micevych, Paul (2003) Visualizing activation of opioid circuits by internalization of G protein-coupled receptors. Mol Neurobiol 27:197-222
Micevych, P; Sinchak, K (2001) Estrogen and endogenous opioids regulate CCK in reproductive circuits. Peptides 22:1235-44
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Holland, K L; Norby, L A; Micevych, P E (1998) Peripubertal ontogeny and estrogen stimulation of cholecystokinin and preproenkephalin mRNA in the rat hypothalamus and limbic system. J Comp Neurol 392:48-57
Holland, K; Norell, A; Micevych, P (1998) Interaction of thyroxine and estrogen on the expression of estrogen receptor alpha, cholecystokinin, and preproenkephalin messenger ribonucleic acid in the limbic-hypothalamic circuit. Endocrinology 139:1221-8
Eckersell, C B; Popper, P; Micevych, P E (1998) Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 18:3967-76
Sinchak, K; Hendricks, D G; Baroudi, R et al. (1997) Orphanin FQ/nociceptin in the ventromedial nucleus facilitates lordosis in female rats. Neuroreport 8:3857-60
Eckersell, C B; Micevych, P E (1997) Opiate receptors modulate estrogen-induced cholecystokinin and tachykinin but not enkephalin messenger RNA levels in the limbic system and hypothalamus. Neuroscience 80:473-85
Blanco, C E; Popper, P; Micevych, P (1997) Anabolic-androgenic steroid induced alterations in choline acetyltransferase messenger RNA levels of spinal cord motoneurons in the male rat. Neuroscience 78:873-82
Holland, K L; Popper, P; Micevych, P E (1997) Infusion of CCK-A receptor mRNA antisense oligodeoxynucleotides inhibits lordosis behavior. Physiol Behav 62:537-43

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