Estrogen has profound effects on the structure and function of the CNS. Recent evidence that estrogen has neuroprotective effects and enhances spine density in the hippocampus have made the study of estrogenic activation of the CNS an interesting and timely topic. Much of our understanding of estrogen's actions in the brain is derived from studying steroid responsive cells and circuits that regulate reproductive behaviors. The present proposal is focused on the interaction of two transmitter systems, cholecystokinin (CCK) and endogenous opioid peptides (EOP) in a classic steroid sensitive system that regulates lordosis, the limbic-hypothalamic circuit. These transmitters are highly regulated by estrogen, and both alter reproductive behavior. Our working hypothesis for this proposal is that estrogen alters the interaction among the EOP and CCK systems. Preliminary results suggest that delta opioid receptors mediate estrogen-induced CCK expression, and mu opioid receptors mediate CCK release. We propose five experiments to test parts of this general hypothesis. In the first experiment, we will determine the dependence of estrogen-induced CCK release on increased CCK mRNA expression. The second experiment, using receptor and GTPgammaS binding, will characterize the functional coupling of mu- and delta-opioid receptors in response to estrogen stimulation. The third experiment, using colocalization studies, will provide morphological evidence for direct versus indirect opioid effects on CCK cells. The fourth experiment, using microdialysis and behavioral testing, will provide direct evidence of a functional interaction of CCK and EOP. Finally, in experiment five, using both in vitro and in vivo assays, we will test the interaction of opioids at the CCK receptor and vice versa. These experiments will not only tell us about the actions of steroids in specific circuits, but they will also provide important information about the interactions of neuropeptide circuits regulating behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039495-03
Application #
6477159
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Edwards, Emmeline
Project Start
1999-12-10
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
3
Fiscal Year
2002
Total Cost
$292,853
Indirect Cost
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Micevych, Paul E; Kelly, Martin J (2012) Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology 96:103-10
Sinchak, Kevin; Mills, Richard H; Eckersell, Clair B et al. (2004) Medial preoptic area delta-opioid receptors inhibit lordosis. Behav Brain Res 155:301-6
Chaban, V V; Mayer, E A; Ennes, H S et al. (2003) Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons. Neuroscience 118:941-8
Micevych, Paul E; Rissman, Emilie F; Gustafsson, Jan-Ake et al. (2003) Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization. J Neurosci Res 71:802-10
Sinchak, Kevin; Mills, Richard H; Tao, Leslie et al. (2003) Estrogen induces de novo progesterone synthesis in astrocytes. Dev Neurosci 25:343-8
Sinchak, Kevin; Micevych, Paul (2003) Visualizing activation of opioid circuits by internalization of G protein-coupled receptors. Mol Neurobiol 27:197-222
Micevych, Paul; Sinchak, Kevin; Mills, Richard H et al. (2003) The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology 78:29-35
Micevych, Paul; Chaban, Victor; Quesada, Arnulfo et al. (2002) Oestrogen modulates cholecystokinin: opioid interactions in the nervous system. Pharmacol Toxicol 91:387-97
Mills, Richard H; Romeo, Horacio E; Lu, John K H et al. (2002) Site-specific decrease of progesterone receptor mRNA expression in the hypothalamus of middle-aged persistently estrus rats. Brain Res 955:200-6
Micevych, P; Sinchak, K (2001) Estrogen and endogenous opioids regulate CCK in reproductive circuits. Peptides 22:1235-44

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