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 #
5P01HL018974-23
Application #
6109474
Study Section
Project Start
1999-07-01
Project End
2000-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
23
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
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