The long-term objective of this research is to establish how hormonal signals are recognized by brain cells and subsequently translated into specific changes in behavior. To accomplish this goal, studies are focused on elucidating the mechanisms by which the ovarian steroid hormones regulate the expression of one component of female reproductive behavior, the lordosis response. Previous work has provided evidence that estrogenic facilitation of lordosis involves receptor-mediated regulation of gene expression in neurons of the ventromedial hypothalamus (VMH). The research described in this proposal uses a combination of behavioral and biochemical techniques to test the hypothesis that ovarian steroid induction of lordosis in female rats is mediated by augmentation of norepinephrine (NE) transmission in or near the VMH. Specific experiments will ask: (1) Does steroid activation of lordosis behavior require NE transmission in or near the VMH? If so, which NE receptor subtype(s) mediate the effects of NE on lordosis? (2) Do hormone treatments which facilitate lordosis behavior augment basal and/or evoked release of NE in or near the VMH? (3) Are the facilitatory and inhibitory effects of other neurotransmitters and neuromodulators on steroid-dependent lordosis mediated by alterations in NE release in or near the VMH? (4) Are sex differences in steroid facilitation of lordosis responsiveness due to sex differences in hormonal regulation of NE transmission in or near the VMH? (5) Do ovarian steroids regulate activity of tyrosine hydroxylase, the rate-limiting enzyme in NE synthesis, in or near the VMH? If so, are soluble and/or synaptosomal tyrosine hydroxylase the target of regulation, and what is the mechanism of regulation? The new information provided by these studies will form the foundation for future work, the ultimate goal of which is to define the precise molecular mechanisms by which hormones act in brain tissue to bring about specific behavioral changes. Clarification of the effects of ovarian steroids on NE transmission in the brain may allow us to develop testable hypotheses regarding the relationships among hormones, premenstrual complaints, postmenopausal complaints, stress, depression and anxiety. In addition, studies on sex differences in neurotransmitter regulation might yield insight into sex differences in the occurrence of psychiatric illnesses and the neural responses to therapeutic agents, such as antidepressants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH041414-05
Application #
3486776
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1985-09-01
Project End
1993-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Lebesgue, Diane; Traub, Michael; De Butte-Smith, Maxine et al. (2010) Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats. PLoS One 5:e8642
Lebesgue, D; Reyna-Neyra, A; Huang, X et al. (2009) GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol. J Neuroendocrinol 21:743-52
De Butte-Smith, M; Gulinello, M; Zukin, R S et al. (2009) Chronic estradiol treatment increases CA1 cell survival but does not improve visual or spatial recognition memory after global ischemia in middle-aged female rats. Horm Behav 55:442-53
González-Flores, Oscar; Gómora-Arrati, Porfirio; Garcia-Juárez, Marcos et al. (2009) Nitric oxide and ERK/MAPK mediation of estrous behavior induced by GnRH, PGE2 and db-cAMP in rats. Physiol Behav 96:606-12
Lebesgue, Diane; Chevaleyre, Vivien; Zukin, R Suzanne et al. (2009) Estradiol rescues neurons from global ischemia-induced cell death: multiple cellular pathways of neuroprotection. Steroids 74:555-61
Lee, Anna W; Kyrozis, Andreas; Chevaleyre, Vivien et al. (2008) Estradiol modulation of phenylephrine-induced excitatory responses in ventromedial hypothalamic neurons of female rats. Proc Natl Acad Sci U S A 105:7333-8
Lee, A W; Kyrozis, A; Chevaleyre, V et al. (2008) Voltage-dependent calcium channels in ventromedial hypothalamic neurones of postnatal rats: modulation by oestradiol and phenylephrine. J Neuroendocrinol 20:188-98
Gomora-Arrati, Porfirio; Beyer, Carlos; Lima-Hernandez, Francisco Javier et al. (2008) GnRH mediates estrous behavior induced by ring A reduced progestins and vaginocervical stimulation. Behav Brain Res 187:1-8
Gonzalez-Flores, O; Etgen, A M; Komisaruk, B K et al. (2008) Antagonists of the protein kinase A and mitogen-activated protein kinase systems and of the progestin receptor block the ability of vaginocervical/flank-perineal stimulation to induce female rat sexual behaviour. J Neuroendocrinol 20:1361-7

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