The research proposed in this ADAMHA Research Science Development Award application tests the hypothesis that the ovarian hormones estradiol E2 and progesterone (P) regulate norepinephrine (NE) signal transduction in the neuronal populations which control reproduction. Preliminary work from this laboratory demonstrates that the functional activity of alpha 1 and beta-adrenergic receptors, as reflected by stimulation of brain slice cAMP accumulation and membrane adrenylyl cyclase (AC) activity, is modulated E2 and P female rat hypothalamus and preoptic (POA). E2 attenuates beta- receptor activation of AC and concomitantly increase alpha 1 receptor potentiation of cAMP accumulation in hypothalamic and POA slices. The changes are correlated with modest increases in alpha 1 receptor number but no alteration in beta receptor number or antagonist binding affinity. In slices from E2-primed females, P abolishes alpha 1 receptor augmentation of cAMP synthesis without measurably decreasing alpha 1 receptor binding. Therefore, studies described in this proposal are designed identity the mechanism underlying ovarian steroid regulation of alpha and beta adrenergic receptors in the hypothalamus and POA. Specific hypotheses to be addressed include: A. The alpha adrenergic receptor is a gene product whose expression is regulated by E2-receptor interactions and which is subject to homologous desensitization by P. The following studies will test this hypothesis: (1) Is E2 elevation of alpha 1 receptor number confined to regions of hypothalamus and POA that express E2 receptors and correlated with hormonal facilitation of estrous behavior? (2) Does E2 regulate the level of alp 1 receptor mRNA in regions of the hypothalamus and POA that express E2 receptors? (3) Does P abolish alpha 1 receptor augmentation of cAMP formation in slices from E2-primed rats by modifying alpha 1 receptor coupling to G proteins? (4) Are E2 and P regulation of alpha 1 receptor augmentation of cAMP formation correlated with alterations in alpha 1 receptor coupling to the phosphoinositol second messenger system? B. E2 promote homologous desensitization of beta-adrenergic receptor activation of AC via E2-receptor-mediated interactions. The following studies will test this hypothesis: (1) Does E2 have selective effects on beta 1 and or beta 2 receptor number in discrete hypothalamic regions? (2) Is E2 attenuation of B receptor stimulation of AC mediated by E2-receptor within brain cell nuclei? (3) Does E2 inhibit Beta- adrenergic activation of cyclase by modifying beta receptor coupling to G proteins? (4) Is E2 desensitization of beta-adrenergic coupling to AC correlated with increased expression of beta-arresting mRNA?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research (K02)
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Research Scientist Development Review Committee (MHK)
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Albert Einstein College of Medicine
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Ansonoff, M A; Etgen, A M (2001) Receptor phosphorylation mediates estradiol reduction of alpha2-adrenoceptor coupling to G protein in the hypothalamus of female rats. Endocrine 14:165-74
Acosta-Martinez, M; Fiber, J M; Brown, R D et al. (1999) Localization of alpha1B-adrenergic receptor in female rat brain regions involved in stress and neuroendocrine function. Neurochem Int 35:383-91
Etgen, A M; Chu, H P; Fiber, J M et al. (1999) Hormonal integration of neurochemical and sensory signals governing female reproductive behavior. Behav Brain Res 105:93-103
Fiber, J M; Etgen, A M (1998) Evidence that GABA augmentation of norepinephrine release is mediated by interneurons. Brain Res 790:329-33
Ansonoff, M A; Etgen, A M (1998) Estradiol elevates protein kinase C catalytic activity in the preoptic area of female rats. Endocrinology 139:3050-6
Karkanias, G B; Morales, J C; Etgen, A M (1998) Effects of diabetes and estradiol on norepinephrine release in female rat hypothalamus, preoptic area and cortex. Neuroendocrinology 68:30-6
Vathy, I; Sokol, J; Etgen, A M (1997) Gender-related differences exist in cortical [3H]nisoxetine binding and are not affected by prenatal morphine exposure. Neuroscience 76:331-4
Chu, H P; Etgen, A M (1997) A potential role of cyclic GMP in the regulation of lordosis behavior of female rats. Horm Behav 32:125-32
Karkanias, G B; Li, C S; Etgen, A M (1997) Estradiol reduction of alpha 2-adrenoceptor binding in female rat cortex is correlated with decreases in alpha 2A/D-adrenoceptor messenger RNA. Neuroscience 81:593-7
Fiber, J M; Etgen, A M (1997) GABA augments basal and electrically stimulated 3H-norepinephrine release in hypothalamic, preoptic area and cortical slices of female rats. Neurochem Int 31:769-80

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