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Nuclear and Extranuclear Estrogen Binding Sites in the Rat Forebrain and Autonomic Medullary Areas

Division of Neurobiology (T.A.M.), Department of Neurology and Neuroscience, Weill-Cornell Medical College, New York, New York 10021; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology (T.A.M., B.S.M.), The Rockefeller University, New York, New York 10065; and Departments of Neuroscience (L.S.L.) and Molecular Endocrinology (S.E.A.), Merck Research Laboratories, West Point, Pennsylvania 19486

Address all correspondence and requests for reprints to: Dr. Teresa A. Milner, Division of Neurobiology, Weill-Cornell Medical College, 411 East 69th Street, New York, New York 10021. E-mail: tmilner{at}med.cornell.edu.

Immunocytochemical studies have shown that nuclear and extranuclear estrogen receptors (ERs) are present in several extrahypothalamic brain regions. The goal of this study was to determine the subcellular location of functional ERs, particularly extranuclear ERs, by demonstrating ¹²⁵I-estradiol binding in the rat forebrain and medullary sections prepared for light and electron microscopic autoradiography. Some sections were immunocytochemically labeled with the catecholamine-synthesizing enzyme, tyrosine hydroxylase (TH), prior to the autoradiographic procedure. By light microscopy, dense accumulations of silver grains denoting ¹²⁵I-estradiol binding were observed over cells in the ventromedial and arcuate hypothalamic nuclei, amygdala, and nucleus of the solitary tract. In sections labeled for TH, large accumulations of silver grains were admixed with TH-labeled processes in the medial nucleus of the amygdala and over TH-labeled perikarya in the medial and commissural nucleus of the solitary tract. Electron microscopic analyses were focused on the rostral ventrolateral medulla and the hippocampal CA1 region, two regions previously shown to have extranuclear ERs. In the rostral ventrolateral medulla, silver grains indicative of ¹²⁵I-estradiol binding were found within a few large terminals, affiliated with mitochondria. In the hippocampus, autoradiographic silver grains denoting ¹²⁵I-estradiol binding were associated with mitochondria in dendritic shafts or were near synaptic specializations on dendritic spines. These patterns of silver grain labeling were not seen in sections from rats that received ¹²⁵I-estradiol combined with cold estradiol. The association of ¹²⁵I-estradiol binding with pre- and postsynaptic profiles supports a functional role for nonnuclear ERs in brain.