# NEURAL INFLUENCE ON HYPOPHYSEAL-GONADAL FUNCTION

> **NIH NIH R01** · OREGON REGIONAL PRIMATE RESEARCH CENTER · 1994 · $276,498

## Abstract

Infertility often results from disruption of menstrual cyclicity and/or
ovulation:  processes known to be driven by specific hypothalamic
signals.  By monitoring neurosecretions in either naturally ovulating or
ovariectomized (OVX) rhesus macaques, we observed a 10-fold increase in
gonadotropin-releasing hormone (GnRH) secretion during an estradiol-
17beta (E2)-induced luteinizing hormone (LH) surge.  No less than 14
neurotransmitter/neuropeptide(s) are implicated in the regulation of GnRH
secretion.  Because adrenergic receptors are found on GnRH neurons, we
initially focus on norepinephrine (NE) and neuropeptide Y (NPY), which
are colocalized in noradrenergic cells and stimulate GnRH gene expression
and secretion in E2-conditioned animals, including macaques.  Aim 1a will
resolve if the preovulatory rise in ovarian E2 stimulates NE and NPY
secretion in conjunction with the E2-induced GnRH/LH surge.  Aim 1b will
decipher if blockade of either NE or NPY receptor activity by selective
antagonists blocks the GnRH/LH surge.  Continuous push-pull perfusion or
microdialysis will be performed in the mediobasal hypothalamus (MBH) of
both intact and OVX monkeys with or without treatment of prazosin (NE
antagonist) and (Ac[3-(2,6 dichlorobenzyl)tyr(27,36)D-Thr(32)]NPY-(27-
36)amide (NPY antagonist).  Changes in perfusate levels of NE, NPY and
GnRH will be analyzed by high-performance liquid chromatography and
radioimmunoassays, respectively.  Aim 2 addresses the morphometric and
intracellular evidence of how E2 influences NPY/NE/GnRH secretion.  Aim
2a will determine if estrogen receptors are localized in NE and/or NPY
neurons, if NPY is produced in NE neurons, and if NE/NPY terminals
synapse with hypothalamic GnRH neurons.  Histological sections of the MBH
and brainstem (i.e., locus coeruleus/lateral tegmentum) will be examined
for the localization of neurons that express estrogen receptor mRNAs (by
in situ hybridization) and NE (i.e., dopamine-beta-hydroxylase), NPY and
GnRH (by immunocytochemistry).  Aim 2b will quantitate E2-induced changes
in NPY and NE (i.e., tyrosine hydroxylase) mRNA contents in identified
loci of brainstem and hypothalamus by ribonuclease protection assay.
Aims 3 and 4 examine how synaptic NE secretion interacts with other
putative neuromodulators to regulate GnRH release.  Aim 3a will determine
if blockade of NE transporter activity (presynaptic NE reuptake) by the
antidepressant, desipramine, acutely stimulates NE, hence GnRH, release.
Aim 3b will show that continuous desipramine infusion suppresses NE/GnRH
secretion, and establish if GnRH pulses can be reinitiated by pulses of
NE or neuroexcitatory amino acids (i.e., N-methyl-D,L-aspartate).
Microdialysis cannulae implanted in the MBH of OVX monkeys will be used
for acute (3a) or continuous (3b) desipramine treatment, pulsatile NE or
N-methyl-D,L-aspartate infusion (3b) and microdialysate collection for
NE and GnRH measurements (3a,b).  Aim 4a will examine by in situ
hybridiza...

## Key facts

- **NIH application ID:** 2197332
- **Project number:** 2R01HD016631-11A2
- **Recipient organization:** OREGON REGIONAL PRIMATE RESEARCH CENTER
- **Principal Investigator:** HAROLD G SPIES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $276,498
- **Award type:** 2
- **Project period:** 1982-09-01 → 1999-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2197332

## Citation

> US National Institutes of Health, RePORTER application 2197332, NEURAL INFLUENCE ON HYPOPHYSEAL-GONADAL FUNCTION (2R01HD016631-11A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2197332. Licensed CC0.

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