The C1 adrenergic neurons in the rostral ventrolateral medulla (RVL) are critical for maintaining sympathetic tone. Ultrastructural studies conducted during the presently funded period have provided anatomical evidence that catecholamines and opioids can both directly and indirectly [through gamma-aminobutyric acid (GABA) interneurons] modulate C1 adrenergic neurons via separate, as well as, interrelated mechanisms. Moreover, they have demonstrated that C1 adrenergic terminals co-localize glutamate and form monosynaptic contacts with sympathetic preganglionic neurons (SPNs) located in the intermediolateral cell column (IML) of the thoracic spinal cord. Physiological and pharmacological studies have suggested several models for the receptor-mediated mechanisms by which catecholamines and opioids may modulate C1 adrenergic neurons. However, anatomical support for such models is lacking. Thus, the present project takes advantage of the recent cloning and generation of antisera to catecholamine, opioid and glutamatergic receptors and proposes 3 studies which aim to directly examine the receptor-mediated regulation of C1 adrenergic neurons by these transmitters in the rat, using quantitative light microscopic and electron microscopic immunocytochemistry. Study I will localize alpha2A -adrenergic receptors (alpha2A Ars) in the RVL that may be the substrates for antihypertensive actions of alpha2 -adrenergic drugs. Subsequent studies will differentiate two models of modulation of C1 neurons by determining whether alpha2A Ars in the RVL are located either (a) within C1 neurons at sites postsynaptic to terminals contacting them, including those containing GABA, or (b) in GABAergic terminals presynaptic to reticulospinal neurons. Study II will test the hypothesis that both the diverse physiological effects of opiates in the RVL as well as the heterogeneous cellular relations between endogenous opioid (enkephalin) terminals and C1 adrenergic neurons can be explained by a differential localization of gamma- and sigma-opioid receptors (Ors) at pre- or postsynaptic sites, respectively. In addition, both studies will test the premise that chronic administration of clonidine (Study I) or morphine (Study II) will alter the number and/or cellular distribution of alpha2A Ars or sigma- or gammaORs, respectively, in the RVL. Finally, since C1 adrenergic neurons contain both adrenergic receptors and glutamate, Study III will determine if adrenergic terminals that contact identified SPNs in the IML contain alpha2A Ars at presynaptic sites and/or N-methyl-D- aspartate (NMDA)-type glutamate receptors at pre- and/or postsynaptic sites. These receptors may mediate and/or modulate the activity of the C1 reticulospinal pathway. These studies will yield information that may lead to improved pharmacological treatments for, and further the understanding of the mechanisms of, hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL018974-22S1
Application #
6296850
Study Section
Project Start
1999-04-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
22
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Glass, Michael J; Chan, June; Pickel, Virginia M (2017) Ultrastructural characterization of tumor necrosis factor alpha receptor type 1 distribution in the hypothalamic paraventricular nucleus of the mouse. Neuroscience 352:262-272
Takahashi, Reisuke H; Capetillo-Zarate, Estibaliz; Lin, Michael T et al. (2013) Accumulation of intraneuronal ýý-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses. PLoS One 8:e51965
Misono, K; Lessard, A (2012) Apomorphine-evoked redistribution of neurokinin-3 receptors in dopaminergic dendrites and neuronal nuclei of the rat ventral tegmental area. Neuroscience 203:27-38
Van Kempen, Tracey A; Milner, Teresa A; Waters, Elizabeth M (2011) Accelerated ovarian failure: a novel, chemically induced animal model of menopause. Brain Res 1379:176-87
Williams, Tanya J; Akama, Keith T; Knudsen, Margarete G et al. (2011) Ovarian hormones influence corticotropin releasing factor receptor colocalization with delta opioid receptors in CA1 pyramidal cell dendrites. Exp Neurol 230:186-96
Williams, T J; Milner, T A (2011) Delta opioid receptors colocalize with corticotropin releasing factor in hippocampal interneurons. Neuroscience 179:9-22
Williams, Tanya J; Torres-Reveron, Annelyn; Chapleau, Jeanette D et al. (2011) Hormonal regulation of delta opioid receptor immunoreactivity in interneurons and pyramidal cells in the rat hippocampus. Neurobiol Learn Mem 95:206-20
Spencer-Segal, Joanna L; Waters, Elizabeth M; Bath, Kevin G et al. (2011) Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. J Neurosci 31:6780-90
Williams, Tanya J; Mitterling, Katherine L; Thompson, Louisa I et al. (2011) Age- and hormone-regulation of opioid peptides and synaptic proteins in the rat dorsal hippocampal formation. Brain Res 1379:71-85
Takahashi, Reisuke H; Capetillo-Zarate, Estibaliz; Lin, Michael T et al. (2010) Co-occurrence of Alzheimer's disease ß-amyloid and ? pathologies at synapses. Neurobiol Aging 31:1145-52

Showing the most recent 10 out of 294 publications